ClinVar Genomic variation as it relates to human health
NM_006767.4(LZTR1):c.742G>A (p.Gly248Arg)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(13); Likely pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006767.4(LZTR1):c.742G>A (p.Gly248Arg)
Variation ID: 209088 Accession: VCV000209088.40
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q11.21 22: 20990476 (GRCh38) [ NCBI UCSC ] 22: 21344765 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 11, 2015 Jun 9, 2024 Mar 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006767.4:c.742G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006758.2:p.Gly248Arg missense NC_000022.11:g.20990476G>A NC_000022.10:g.21344765G>A NG_034193.1:g.13208G>A LRG_989:g.13208G>A LRG_989t1:c.742G>A LRG_989p1:p.Gly248Arg Q8N653:p.Gly248Arg - Protein change
- G248R
- Other names
- -
- Canonical SPDI
- NC_000022.11:20990475:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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LZTR1 | - | - |
GRCh38 GRCh37 |
3121 | 3629 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
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Dec 27, 2022 | RCV000191027.21 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Dec 10, 2023 | RCV000413889.25 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763072.10 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001526613.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 16, 2020 | RCV002381647.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 11, 2024 | RCV004525835.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 25, 2024 | RCV003988835.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jul 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000491461.6
First in ClinVar: Jan 09, 2017 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect due to upregulation of the RAS-MAPK signaling pathway (Motta et al., 2019); In silico analysis supports that this … (more)
Published functional studies demonstrate a damaging effect due to upregulation of the RAS-MAPK signaling pathway (Motta et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26446362, 27942422, 31533111, 23917401, 25795793, 28944487, 30481304, 28991257, 30368668, 31324109, 30859559, 31825158, 32981126, 32368696) (less)
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Likely pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Schwannomatosis 2
Noonan syndrome 10
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893582.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 10
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Laboratorio de Biologia Molecular - Genetica, Hospital de Pediatria Garrahan
Accession: SCV000920884.1
First in ClinVar: Dec 17, 2019 Last updated: Dec 17, 2019 |
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Pathogenic
(Sep 03, 2020)
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criteria provided, single submitter
Method: research
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Noonan syndrome 10
Affected status: yes
Allele origin:
paternal
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-SouthSeq
Accession: SCV001439375.1 First in ClinVar: Oct 30, 2020 Last updated: Oct 30, 2020 |
Comment:
ACMG codes:PS3, PS4M, PM1, PM2, PP3
Number of individuals with the variant: 1
Clinical Features:
Congenital cataract (present) , Anemia (present)
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Pathogenic
(May 28, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001474269.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The LZTR1 c.742G>A; p.Gly248Arg variant (rs869320686) is reported in the literature in individuals with Noonan syndrome (Umeki 2018, Jin 2017), is reported to segregate with … (more)
The LZTR1 c.742G>A; p.Gly248Arg variant (rs869320686) is reported in the literature in individuals with Noonan syndrome (Umeki 2018, Jin 2017), is reported to segregate with disease (Yamamoto 2015), and is reported as occurring de novo in some affected individuals (Pagnamenta 2019). The variant is reported as pathogenic or likely pathogenic by several sources in the ClinVar database (Variation ID: 209088) but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 248 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, this variant occurs in the Kelch functional domain and transfected variant protein results in enhanced ERK1/2 photphorylation (Motta 2019). Considering available information, this variant is classified as pathogenic. References: Jin SC et al. Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. Nat Genet. 2017 Nov;49(11):1593-1601. Motta M et al. Dominant Noonan syndrome-causing LZTR1 mutations specifically affect the Kelch domain substrate-recognition surface and enhance RAS-MAPK signaling. Hum Mol Genet. 2019 Mar 15;28(6):1007-1022. Pagnamenta AT et al. Delineation of dominant and recessive forms of LZTR1-associated Noonan syndrome. Clin Genet. 2019 Jun;95(6):693-703. Umeki I et al. Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes. Hum Genet. 2019 Jan;138(1):21-35. Yamamoto GL et al. Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. J Med Genet. 2015 Jun;52(6):413-21. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Fetal cystic hygroma
Affected status: yes
Allele origin:
de novo
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001737043.1
First in ClinVar: Jul 14, 2021 Last updated: Jul 14, 2021 |
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Pathogenic
(Jun 27, 2022)
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criteria provided, single submitter
Method: research
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Noonan syndrome 10
Affected status: yes
Allele origin:
de novo
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Laboratory of Human Genetics, Universidade de São Paulo
Accession: SCV002538635.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
Comment:
This variant meets our criteria to be classified as pathogenic based upon segregation studies, absence from controls, and in-silico evaluation of pathogenicity.
Number of individuals with the variant: 1
Clinical Features:
Microcephaly (present)
Sex: male
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Pathogenic
(Jun 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 10
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002580964.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3, PS4_MOD, PM1, PM2_SUP, PP3
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Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Apr 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 10
Affected status: yes
Allele origin:
de novo
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Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues
Accession: SCV003035477.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
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Pathogenic
(Nov 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 10
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807394.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM5 moderated, PM6 moderated, PP1 supporting, PP3 supporting
Number of individuals with the variant: 1
Clinical Features:
Split foot (present) , Abnormal hair morphology (present) , Birth length less than 3rd percentile (present) , Micrognathia (present) , Split hand (present) , Premature … (more)
Split foot (present) , Abnormal hair morphology (present) , Birth length less than 3rd percentile (present) , Micrognathia (present) , Split hand (present) , Premature birth (present) , Small for gestational age (present) , Atrial septal defect (present) (less)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
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Pathogenic
(Dec 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 10
Affected status: yes
Allele origin:
de novo
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV004013980.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
PS2, PS3, PM1, PM2, PM5, PP3, PP5
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Pathogenic
(Dec 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001229241.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 248 of the LZTR1 protein (p.Gly248Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 248 of the LZTR1 protein (p.Gly248Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 25795793, 30368668, 30859559). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 209088). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LZTR1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects LZTR1 function (PMID: 30481304). For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Mar 25, 2024)
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criteria provided, single submitter
Method: research
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Schwannomatosis 2
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004805425.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Mar 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001338505.3
First in ClinVar: Jun 18, 2020 Last updated: May 12, 2024 |
Comment:
Variant summary: BRCA2 c.742G>A (p.Ala248Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: BRCA2 c.742G>A (p.Ala248Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.3e-05 in 298566 control chromosomes (gnomAD, Bodian_2014, Fackenthal_2005, Momozawa_2018), predominantly at a frequency of 0.00031 within the African or African-American subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.742G>A has been reported in the literature in individuals affected with breast cancer (example: Gao_2000, Haffty_2006, Maxwell_2015, Dorling_2021), however, it was also found in healthy controls (example: Bodian_2014, Momozawa_2018, Dorling_2021, FLOSSIES database). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. This variant was found co-occurring with another pathogenic BRCA2 variant via internal testing (BRCA2 c.5164_5165delAG, p.Ser1722fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters have assessed the variant since 2014: five have classified the variant as of uncertain significance, three as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Pathogenic
(Oct 16, 2020)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Hereditary cancer-predisposing syndrome
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002668511.2
First in ClinVar: Nov 29, 2022 Last updated: Jun 09, 2024 |
Comment:
The p.G248R pathogenic mutation (also known as c.742G>A), located in coding exon 8 of the LZTR1 gene, results from a G to A substitution at … (more)
The p.G248R pathogenic mutation (also known as c.742G>A), located in coding exon 8 of the LZTR1 gene, results from a G to A substitution at nucleotide position 742. The glycine at codon 248 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in multiple individuals with a clinical diagnosis of autosomal dominant Noonan syndrome, and has been shown to segregate with disease in several families (Güemes M et al. Horm Res Paediatr, 2019 Sep;92:269-275; Chinton J et al. Am J Med Genet A, 2020 02;182:409-414; Yamamoto GL et al. J Med Genet, 2015 Jun;52:413-21). This alteration has also been shown as a recurrent de novo alteration in individuals with autosomal dominant Noonan syndrome (Chinton J et al. Am J Med Genet A, 2020 02;182:409-414). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is pathogenic for autosomal dominant Noonan syndrome; however, the association of this alteration with an increased risk of LZTR1-related schwannomatosis (SWN) is unknown. (less)
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Pathogenic
(Jun 01, 2015)
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no assertion criteria provided
Method: literature only
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NOONAN SYNDROME 10
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000246007.2
First in ClinVar: Sep 29, 2015 Last updated: Oct 11, 2015 |
Comment on evidence:
In 3 members of a Brazilian family (Br-F3) with Noonan syndrome-10 (NS10; 616564), Yamamoto et al. (2015) identified a heterozygous c.742G-A transition (c.742G-A, NM_006767.3) in … (more)
In 3 members of a Brazilian family (Br-F3) with Noonan syndrome-10 (NS10; 616564), Yamamoto et al. (2015) identified a heterozygous c.742G-A transition (c.742G-A, NM_006767.3) in exon 8 of the LZTR1 gene, resulting in a gly248-to-arg (G248R) substitution in the KT4 domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the 1000 Genomes Project and Exome Sequencing Project databases and 609 Brazilian controls. Functional studies of the variant were not performed. Steklov et al. (2018) found that LZTR1 Kelch domain mutants, including G248R, showed decreased binding to RAS in coimmunoprecipitation assays. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001741682.3 First in ClinVar: May 10, 2021 Last updated: Sep 08, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001953290.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Noonan syndrome 10
Affected status: yes
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV001423246.1
First in ClinVar: Jul 19, 2020 Last updated: Jul 19, 2020 |
Comment:
Variant interpretted as Pathogenic and reported on 01-22-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpretted as Pathogenic and reported on 01-22-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Abnormality of cardiovascular system morphology (present)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: female
Method: Sanger Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2019-01-22
Testing laboratory interpretation: Pathogenic
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Providing more evidence on LZTR1 variants in Noonan syndrome patients. | Chinton J | American journal of medical genetics. Part A | 2020 | PMID: 31825158 |
Delineation of dominant and recessive forms of LZTR1-associated Noonan syndrome. | Pagnamenta AT | Clinical genetics | 2019 | PMID: 30859559 |
Dominant Noonan syndrome-causing LZTR1 mutations specifically affect the Kelch domain substrate-recognition surface and enhance RAS-MAPK signaling. | Motta M | Human molecular genetics | 2019 | PMID: 30481304 |
Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes. | Umeki I | Human genetics | 2019 | PMID: 30368668 |
LZTR1 is a regulator of RAS ubiquitination and signaling. | Bigenzahn JW | Science (New York, N.Y.) | 2018 | PMID: 30442766 |
Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination. | Steklov M | Science (New York, N.Y.) | 2018 | PMID: 30442762 |
Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. | Yamamoto GL | Journal of medical genetics | 2015 | PMID: 25795793 |
Text-mined citations for rs869320686 ...
HelpRecord last updated Jun 10, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.