ClinVar Miner

Submissions for variant NM_001927.4(DES):c.365A>G (p.Tyr122Cys)

dbSNP: rs1400593451
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000757150 SCV000885276 uncertain significance not provided 2017-07-21 criteria provided, single submitter clinical testing The p.Tyr122Cys is absent from general population databases such as 1000 Genomes, NHLBI GO Exome Sequencing Project (ESP), and the Exome Aggregation Consortium (ExAC) browser. The tyrosine at position 122 is highly conserved considering ten species (Alamut v2.9.0) and computational analyses of the effects of the p.Tyr122Cys variant on protein structure and function is deleterious (SIFT: damaging, MutationTaster: probably damaging, PolyPhen-2: disease causing). Comparing rare variants in a cohort of patients with ARCV against frequencies in ExAC, Walsh et al. (2017) classify the p.Tyr122Cys variant as likely pathogenic; however the variant was observed in only one patient. Altogether, there is not enough evidence to classify the p.Tyr122Cys variant with certainty.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego RCV000852535 SCV000995233 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2018-01-03 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001171066 SCV001333736 likely pathogenic Cardiomyopathy 2021-02-23 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001855888 SCV002168324 uncertain significance Desmin-related myofibrillar myopathy 2021-11-18 criteria provided, single submitter clinical testing 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. Experimental studies have shown that this missense change affects DES function (PMID: 31718026). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 618590). This missense change has been observed in individual(s) with clinical features of arrhythmogenic right ventricular cardiomyopathy (PMID: 27532257). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 122 of the DES protein (p.Tyr122Cys).

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