ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.716T>C (p.Val239Ala) (rs200997703)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037314 SCV000060971 uncertain significance not specified 2012-05-31 criteria provided, single submitter clinical testing The Val239Ala variant in DSG2 has been reported in 1 individual with ARVC and wa s absent from 600 control chromosomes (Quarta 2011). This variant has also been identified in 2/3136 African American chromosomes from a broad population by the NHLBI Exome Sequencing Project ( Valine (Val) at position 239 is highly conserved in mammal and evolutionarily distant specie s, though computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to t he protein. Additional information is needed to fully assess the clinical signif icance of the Val239Ala variant.
Invitae RCV001086638 SCV000551012 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-10-28 criteria provided, single submitter clinical testing
GeneDx RCV000766364 SCV000566926 uncertain significance not provided 2018-11-08 criteria provided, single submitter clinical testing The V239A variant of uncertain significance in the DSG2 gene has been reported in at least one individual meeting task force criteria for ARVC; however, detailed clinical data, segregation data and functional data were not provided (Quarta et al., 2011). This variant is observed in 27/23992 (0.1%) alleles from individuals of African ancestry in large population cohorts, indicating it may be a rare benign variant in this population (Lek et al., 2016). The V239A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nevertheless, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Ambry Genetics RCV000621582 SCV000734921 likely benign Cardiovascular phenotype 2020-07-20 criteria provided, single submitter clinical testing Subpopulation frequency in support of benign classification
Color Health, Inc RCV001186663 SCV001353202 likely benign Cardiomyopathy 2020-02-21 criteria provided, single submitter clinical testing
Genetics and Genomics Program,Sidra Medicine RCV001293112 SCV001434102 uncertain significance Primary dilated cardiomyopathy criteria provided, single submitter research
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000766364 SCV000924772 uncertain significance not provided 2016-05-11 no assertion criteria provided provider interpretation p.Val239Ala (c.716T>C) in DSG2 (NM_001943.3) We have seen this variant in a patient with a TIA at a young age and a family history of early stroke, sudden death, and cardiomyopathy. We did not see evidence of ARVC in the family though only minimal data is available on the relative with cardiomyopathy and sudden death. Given the frequency in the general population, we consider this variant a variant of uncertain significance, probably benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Per the lab report, the variant has been reported in at least one case of ARVC (Quarta et al 2011). Per the lab report, "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." Per the lab report, "This variant is present in population databases (rs200997703, ExAC 0.1%)."

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