ClinVar Genomic variation as it relates to human health
NM_024422.6(DSC2):c.1034T>C (p.Ile345Thr)
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.
Likely pathogenic(1); Uncertain significance(6)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_024422.6(DSC2):c.1034T>C (p.Ile345Thr)
Variation ID: 241471 Accession: VCV000241471.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31082969 (GRCh38) [ NCBI UCSC ] 18: 28662935 (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 Jul 1, 2016 May 1, 2024 Jan 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024422.6:c.1034T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_077740.1:p.Ile345Thr missense NM_004949.5:c.1034T>C NP_004940.1:p.Ile345Thr missense NC_000018.10:g.31082969A>G NC_000018.9:g.28662935A>G NG_008208.2:g.24457T>C LRG_400:g.24457T>C - Protein change
- I345T
- Other names
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- Canonical SPDI
- NC_000018.10:31082968:A:G
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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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
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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DSC2 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1560 | 1695 |
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
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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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Uncertain significance (1) |
criteria provided, single submitter
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Dec 19, 2023 | RCV000226472.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 22, 2020 | RCV000619062.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 3, 2019 | RCV000853178.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 18, 2023 | RCV001524120.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 7, 2022 | RCV001569022.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 19, 2024 | RCV003987471.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 11, 2024 | RCV003998886.2 |
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
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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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Likely pathogenic
(Jul 03, 2019)
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criteria provided, single submitter
Method: research
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Arrhythmogenic right ventricular cardiomyopathy
Affected status: yes
Allele origin:
germline
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Klaassen Lab, Charite University Medicine Berlin
Accession: SCV000995893.1
First in ClinVar: Oct 19, 2019 Last updated: Oct 19, 2019 |
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Uncertain significance
(Sep 07, 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: SCV001792999.3
First in ClinVar: Aug 21, 2021 Last updated: Mar 04, 2023 |
Comment:
Reported in a pediatric patient with ARVC who also harbored a truncating variant in the DSG2 gene (Kuhnisch et al., 2019), although no informative segregation … (more)
Reported in a pediatric patient with ARVC who also harbored a truncating variant in the DSG2 gene (Kuhnisch et al., 2019), although no informative segregation data are available; Also observed in 16 individuals from a cohort of 30,716 individuals who underwent exome sequencing, and none of these individuals had a diagnosis of ARVC based on review of existing electronic health records (Haggerty et al., 2017); Expression studies in neonatal rat cardiomyocytes and cultured mouse cardiac muscle cells (HL-1 cells) suggest that I345T may impact proper cellular localization of desmocollin-2 protein (Beffagna et al., 2007); however, the clinical validity of these studies remains to be determined; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17963498, 20197793, 24070718, 26310507, 26138720, 28471438, 31333075, 31568572, 31402444, 32466575) (less)
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Uncertain significance
(Dec 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 11
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000290725.7
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 345 of the DSC2 protein (p.Ile345Thr). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 345 of the DSC2 protein (p.Ile345Thr). This variant is present in population databases (rs777688726, gnomAD 0.003%). This missense change has been observed in individual(s) with arrhythmogenic cardiomyopathy (PMID: 17963498, 28471438, 35819174). ClinVar contains an entry for this variant (Variation ID: 241471). 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 DSC2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects DSC2 function (PMID: 17963498). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(May 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001733889.2
First in ClinVar: Jun 19, 2021 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces isoleucine with threonine at codon 345 of the DSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces isoleucine with threonine at codon 345 of the DSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant affects the intracellular localization of the DSC2 protein (PMID: 17963498). This variant has been reported in two unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 17963498, 31568572). One of these individuals also carried a truncation variant in the DSG2 gene (PMID: 31568572). This variant has been identified in 2/251066 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jan 19, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004803904.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Comment:
Variant summary: DSC2 c.1034T>C (p.Ile345Thr) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Five of … (more)
Variant summary: DSC2 c.1034T>C (p.Ile345Thr) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251066 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1034T>C has been reported in the literature in individuals affected with Arrhythmogenic cardiomyopathy (e.g. Goudal_2022), individuals affected or unaffected with Arrhythmogenic Right Ventricular Cardiomyopathy (e.g. Beffagna_2007, Christensen_ 2021), or pediatric cardiomyopathy with an additional reported DSG2 variant (e.g. Kuhnisch_2019), in all cases without evidence of causality. These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. One publication reports experimental evidence evaluating an impact on protein function, showing the variant results in abberrant cytoplasmic localization away from cell membrane in cultured cardiomyocytes (e.g. Beffagna_2007), however, effect in disease remains unknown. The following publications have been ascertained in the context of this evaluation (PMID: 17963498, 34400560, 35819174, 28471438, 31568572). ClinVar contains an entry for this variant (Variation ID: 241471). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain Significance
(Jan 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial isolated arrhythmogenic right ventricular dysplasia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004816184.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces isoleucine with threonine at codon 345 of the DSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces isoleucine with threonine at codon 345 of the DSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant affects the intracellular localization of the DSC2 protein (PMID: 17963498). This variant has been reported in two unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 17963498, 31568572). One of these individuals also carried a truncation variant in the DSG2 gene (PMID: 31568572). This variant has been identified in 2/251066 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 11
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Uncertain significance
(Jan 22, 2020)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000735575.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The p.I345T variant (also known as c.1034T>C), located in coding exon 8 of the DSC2 gene, results from a T to C substitution at nucleotide … (more)
The p.I345T variant (also known as c.1034T>C), located in coding exon 8 of the DSC2 gene, results from a T to C substitution at nucleotide position 1034. The isoleucine at codon 345 is replaced by threonine, an amino acid with similar properties. This alteration has been detected in arrhythmogenic right ventricular cardiomyopathy (ARVC) and pediatric cardiomyopathy cohorts (Beffagna G et al. BMC Med. Genet. 2007;8:65; Kühnisch J et al. Clin. Genet., 2019 Dec;96:549-559). In vitro studies have suggested that this variant alters the localization of the DSC2 protein; however, the clinical significance of this mislocalization is uncertain (Beffagna G et al. BMC Med. Genet. 2007;8:65). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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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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Burden of rare variants in arrhythmogenic cardiomyopathy with right dominant form-associated genes provides new insights for molecular diagnosis and clinical management. | Goudal A | Human mutation | 2022 | PMID: 35819174 |
Genotype-phenotype correlation in arrhythmogenic right ventricular cardiomyopathy-risk of arrhythmias and heart failure. | Christensen AH | Journal of medical genetics | 2022 | PMID: 34400560 |
Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3. | Kühnisch J | Clinical genetics | 2019 | PMID: 31568572 |
RIKADA Study Reveals Risk Factors in Pediatric Primary Cardiomyopathy. | Al-Wakeel-Marquard N | Journal of the American Heart Association | 2019 | PMID: 31333075 |
Electronic health record phenotype in subjects with genetic variants associated with arrhythmogenic right ventricular cardiomyopathy: a study of 30,716 subjects with exome sequencing. | Haggerty CM | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28471438 |
Phenotypic expression is a prerequisite for malignant arrhythmic events and sudden cardiac death in arrhythmogenic right ventricular cardiomyopathy. | Zorzi A | Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology | 2016 | PMID: 26138720 |
Compound and digenic heterozygosity predicts lifetime arrhythmic outcome and sudden cardiac death in desmosomal gene-related arrhythmogenic right ventricular cardiomyopathy. | Rigato I | Circulation. Cardiovascular genetics | 2013 | PMID: 24070718 |
The p.A897KfsX4 frameshift variation in desmocollin-2 is not a causative mutation in arrhythmogenic right ventricular cardiomyopathy. | De Bortoli M | European journal of human genetics : EJHG | 2010 | PMID: 20197793 |
Missense mutations in desmocollin-2 N-terminus, associated with arrhythmogenic right ventricular cardiomyopathy, affect intracellular localization of desmocollin-2 in vitro. | Beffagna G | BMC medical genetics | 2007 | PMID: 17963498 |
Text-mined citations for rs777688726 ...
HelpRecord last updated May 08, 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.