rs777688726
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_024422.6(DSC2):āc.1034T>Cā(p.Ile345Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,613,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I345V) has been classified as Uncertain significance.
Frequency
Consequence
NM_024422.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSC2 | NM_024422.6 | c.1034T>C | p.Ile345Thr | missense_variant | 8/16 | ENST00000280904.11 | |
DSC2 | NM_004949.5 | c.1034T>C | p.Ile345Thr | missense_variant | 8/17 | ||
DSC2 | NM_001406506.1 | c.605T>C | p.Ile202Thr | missense_variant | 8/16 | ||
DSC2 | NM_001406507.1 | c.605T>C | p.Ile202Thr | missense_variant | 8/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSC2 | ENST00000280904.11 | c.1034T>C | p.Ile345Thr | missense_variant | 8/16 | 1 | NM_024422.6 | P1 | |
DSC2 | ENST00000251081.8 | c.1034T>C | p.Ile345Thr | missense_variant | 8/17 | 1 | |||
DSC2 | ENST00000648081.1 | c.605T>C | p.Ile202Thr | missense_variant | 9/17 | ||||
DSC2 | ENST00000682357.1 | c.605T>C | p.Ile202Thr | missense_variant | 8/16 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152268Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251066Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135720
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461272Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 726948
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152268Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74390
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Klaassen Lab, Charite University Medicine Berlin | Jul 03, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 19, 2024 | 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. - |
Arrhythmogenic right ventricular dysplasia 11 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 19, 2023 | 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. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 18, 2023 | 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 07, 2022 | 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) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 22, 2020 | 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. - |
Familial isolated arrhythmogenic right ventricular dysplasia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 11, 2024 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at