ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.3764G>A (p.Arg1255Lys)

dbSNP: rs777407386
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV000845316 SCV000987358 uncertain significance Primary familial dilated cardiomyopathy criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001191442 SCV001359263 uncertain significance Cardiomyopathy 2023-07-31 criteria provided, single submitter clinical testing This missense variant replaces arginine with lysine at codon 1255 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional assays have not been performed for this variant. This variant has been reported in three individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 15941723, 20152563, 24070718, 27532257, 26138720), including two individuals who also carried a pathogenic PKP2 truncation variant that could explain the observed phenotype (PMID: 20152563, 24070718). This variant has also been identified in 5/250734 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Invitae RCV001373346 SCV001570056 uncertain significance Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 2023-06-28 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 684783). This missense change has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 15941723, 27532257). This variant is present in population databases (rs777407386, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 1255 of the DSP protein (p.Arg1255Lys).
Ambry Genetics RCV002345928 SCV002623191 uncertain significance Cardiovascular phenotype 2021-01-27 criteria provided, single submitter clinical testing The p.R1255K variant (also known as c.3764G>A), located in coding exon 23 of the DSP gene, results from a G to A substitution at nucleotide position 3764. The arginine at codon 1255 is replaced by lysine, an amino acid with highly similar properties. This variant was identified in an individual who met revised arrhythmogenic right ventricular cardiomyopathy (ARVC) Task Force criteria and also had two variants in another cardiac-related gene. Additionally, the DSP p.R1255K variant did not segregate consistently among this individual's affected relatives (Xu T et al. J Am Coll Cardiol, 2010 Feb;55:587-97). This alteration has also been detected in other ARVC cohorts; however, clinical details were limited, and the same individuals from overlapping cohorts may have been reported multiple times (Bauce B et al. Eur Heart J, 2005 Aug;26:1666-75; Walsh R et al. Genet Med, 2017 02;19:192-203; Rigato I et al. Circ Cardiovasc Genet, 2013 Dec;6:533-42; Zorzi A et al. Europace, 2016 Jul;18:1086-94). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002495208 SCV002779660 uncertain significance Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8; Lethal acantholytic epidermolysis bullosa; Woolly hair-skin fragility syndrome; Keratosis palmoplantaris striata 2; Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis 2021-10-16 criteria provided, single submitter clinical testing

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