ClinVar Genomic variation as it relates to human health
NM_005343.4(HRAS):c.173C>T (p.Thr58Ile)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_005343.4(HRAS):c.173C>T (p.Thr58Ile)
Variation ID: 12610 Accession: VCV000012610.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 533883 (GRCh38) [ NCBI UCSC ] 11: 533883 (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 Sep 7, 2014 May 12, 2024 Apr 3, 2017 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005343.4:c.173C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005334.1:p.Thr58Ile missense NM_176795.5:c.173C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_789765.1:p.Thr58Ile missense NM_001130442.3:c.173C>T NP_001123914.1:p.Thr58Ile missense NM_001318054.2:c.-147C>T 5 prime UTR NC_000011.10:g.533883G>A NC_000011.9:g.533883G>A NG_007666.1:g.6668C>T LRG_506:g.6668C>T LRG_506t1:c.173C>T LRG_506p1:p.Thr58Ile P01112:p.Thr58Ile - Protein change
- T58I
- Other names
- NM_176795.4(HRAS):c.173C>T
- Canonical SPDI
- NC_000011.10:533882: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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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HRAS | No evidence available | No evidence available |
GRCh38 GRCh38 GRCh37 |
9 | 708 | |
LRRC56 | - | - |
GRCh38 GRCh38 GRCh37 |
340 | 1039 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 (7) |
reviewed by expert panel
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Apr 3, 2017 | RCV000013444.32 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2023 | RCV003221783.8 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
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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
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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
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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
(Apr 03, 2017)
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reviewed by expert panel
Method: curation
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Costello syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen RASopathy Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV000616365.4 First in ClinVar: Dec 19, 2017 Last updated: Dec 11, 2022 |
Comment:
The c.173C>T (p.Thr58Ile) variant in HRAS has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of … (more)
The c.173C>T (p.Thr58Ile) variant in HRAS has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 20112233, 16474405). Also, at least 2 independent occurrences of this variant have been detected in patients with a RASopathy (PS4_Supporting; PMID: 22488832, 18247425, 23321623, 20949621, 16921267). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The p.Thr58Ile variant in HRAS is analogous to the same previously established amino acid change in the KRAS gene and the ClinGen RASopathy Expert Panel has defined that the pathogenicities of analogous variants in the HRAS and KRAS genes are correlated based on the assumption that a known functional residue in one gene is equivalent to other functions within that subgroup (PS1; 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of HRAS (PM1; PMID 29493581). The variant is in HRAS, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Thr58Ile variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6, PS4_Supporting, PM2, PS1, PM1, PP2, PP3. (less)
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Pathogenic
(Jun 12, 2020)
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criteria provided, single submitter
Method: clinical testing
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Costello syndrome
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556564.2
First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022 |
Comment:
PS1, PS4_supporting, PM1, PM2, PP5 The HRAS c.173C>T variant is a single nucleotide change from a cytosine to a thymine at position 173 which is … (more)
PS1, PS4_supporting, PM1, PM2, PP5 The HRAS c.173C>T variant is a single nucleotide change from a cytosine to a thymine at position 173 which is predicted to substitute the amino acid threonine at position 58 in the protein to isoleucine. The variant is located in exon 3. This variant has been reported in the literature in patients with Costello syndrome, and this particular variant appears to be associated with an attenuated phenotype and has been described in a father and son (PMID: 22488832; PMID: 18247425) (PS4_supporting). The variant is in dbSNP (rs121917758) but is absent from population databases (PM2). This variant has been classified by the ClinGen RASopathy Variant Curation Expert Panel as Pathogenic and is reported as Pathogenic in the ClinVar database (Variation ID: 12610) (PP5). This variant was detected in both the affected child and her mother. (less)
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Pathogenic
(Jan 01, 2023)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV003916655.8
First in ClinVar: Apr 23, 2023 Last updated: May 12, 2024 |
Comment:
HRAS: PS2, PM1, PM2, PS4:Moderate, PP3
Number of individuals with the variant: 1
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Pathogenic
(Sep 23, 2014)
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criteria provided, single submitter
Method: clinical testing
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Costello syndrome
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000062127.5
First in ClinVar: May 03, 2013 Last updated: Dec 19, 2017 |
Comment:
The Thr58Ile variant in HRAS has been reported in three individuals with clinica l features of Costello syndrome (Gripp 2008, Gripp 2012, LMM unpublished data). … (more)
The Thr58Ile variant in HRAS has been reported in three individuals with clinica l features of Costello syndrome (Gripp 2008, Gripp 2012, LMM unpublished data). It was identified to occur de novo in two of these individuals and segregated w ith disease in one affected relative from one of these families. This variant wa s absent from large population studies. Computational prediction tools and conse rvation analysis suggest that this variant may impact the protein, though this i nformation is not predictive enough to determine pathogenicity. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partner s.org/LMM). (less)
Number of individuals with the variant: 1
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Pathogenic
(Sep 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Costello syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002769451.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Costello syndrome (MIM#218040) [PMID: 31222966]. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews).(I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants in the Ras domain (Decipher; PMID 29493581). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as de novo in at least two individuals with Costello syndrome (PMID 18247425; PMID 26888048). It has also been reported in a father and child with an attenuated Costello syndrome phenotype (PMID 22488832). This variant has been classified as pathogenic by the ClinGen RASopathy Variant Curation Expert Panel (ClinVar). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Jun 28, 2018)
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criteria provided, single submitter
Method: clinical testing
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Costello syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001587697.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to … (more)
Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed to be de novo in individuals with clinical features of Costello syndrome (PMID: 18247425, 22488832, 26888048). ClinVar contains an entry for this variant (Variation ID: 12610). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 58 of the HRAS protein (p.Thr58Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 15, 2008)
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no assertion criteria provided
Method: literature only
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COSTELLO SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033691.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 08, 2016 |
Comment on evidence:
In a boy with Costello syndrome (218040), Gripp et al. (2008) identified a heterozygous de novo 173C-T transition in exon 3 of the HRAS gene, … (more)
In a boy with Costello syndrome (218040), Gripp et al. (2008) identified a heterozygous de novo 173C-T transition in exon 3 of the HRAS gene, resulting in a thr58-to-ile (T58I) substitution in a highly conserved residue in the switch II region of small GTPases. Neither parent carried the mutation, which was present on the paternal allele. At the time of birth, the father and mother were 45 and 34 years old, respectively. The facial features of the patient were less coarse than typical Costello syndrome, but he showed other typical features, including failure to thrive, cognitive impairment, lax skin, deep palmar creases, and pyloric stenosis. (less)
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Pathogenic
(Feb 03, 2014)
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no assertion criteria provided
Method: clinical testing
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Costello syndrome
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000188769.1
First in ClinVar: Sep 07, 2014 Last updated: Sep 07, 2014 |
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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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Costello syndrome: Clinical phenotype, genotype, and management guidelines. | Gripp KW | American journal of medical genetics. Part A | 2019 | PMID: 31222966 |
ClinGen's RASopathy Expert Panel consensus methods for variant interpretation. | Gelb BD | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29493581 |
The rare Costello variant HRAS c.173C>T (p.T58I) with severe neonatal hypertrophic cardiomyopathy. | Hiippala A | American journal of medical genetics. Part A | 2016 | PMID: 26888048 |
Prenatal diagnostic testing of the Noonan syndrome genes in fetuses with abnormal ultrasound findings. | Croonen EA | European journal of human genetics : EJHG | 2013 | PMID: 23321623 |
Transmission of the rare HRAS mutation (c. 173C > T; p.T58I) further illustrates its attenuated phenotype. | Gripp KW | American journal of medical genetics. Part A | 2012 | PMID: 22488832 |
Germline KRAS mutations cause aberrant biochemical and physical properties leading to developmental disorders. | Gremer L | Human mutation | 2011 | PMID: 20949621 |
Prenatal detection of Noonan syndrome by mutation analysis of the PTPN11 and the KRAS genes. | Houweling AC | Prenatal diagnosis | 2010 | PMID: 20112233 |
Costello syndrome associated with novel germline HRAS mutations: an attenuated phenotype? | Gripp KW | American journal of medical genetics. Part A | 2008 | PMID: 18247425 |
Germline mutations in components of the Ras signaling pathway in Noonan syndrome and related disorders. | Kratz CP | Cell cycle (Georgetown, Tex.) | 2006 | PMID: 16921267 |
Germline KRAS mutations cause Noonan syndrome. | Schubbert S | Nature genetics | 2006 | PMID: 16474405 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/4fa14d9d-3bce-4dd8-affa-771b6298c4fc | - | - | - | - |
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Text-mined citations for rs121917758 ...
HelpRecord last updated May 12, 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.