ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.1067C>A (p.Thr356Lys) (rs780626687)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000590097 SCV000233575 uncertain significance not provided 2017-10-30 criteria provided, single submitter clinical testing p.Thr356Lys (ACG>AAG): c.1067 C>A in exon 9 of the DSP gene (NM_004415.2). The Thr356Lys variant in the DSP gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Thr356Lys results in a semi-conservative amino acid substitution of a neutral Threonine with a positively-charged Lysine at a position that is well conserved across species. Consequently, in silico analysis predicts Thr356Lys is damaging to the protein structure/function. The Thr356Lys variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, mutations in nearby residues have not been reported, indicating this region of the protein may tolerate change. With the clinical and molecular information available at this time, we cannot definitively determine if Thr356Lys is a disease-causing mutation or a rare benign variant. The variant is found in ARVC panel(s).
Integrated Genetics/Laboratory Corporation of America RCV000590097 SCV000698416 uncertain significance not provided 2016-08-09 criteria provided, single submitter clinical testing Variant summary: The c.1067C>A (p.Thr356Lys) in DSP gene is a missense change that involves a conserved nucleotide and 4/4 in silico tools predict deleterious outcome. The variant of interest is located in the spectrin repeat domain that is known to be involved in cytoskeletal structure. The variant is absent from control dataset of ExAC. This variant has been observed in 1 family with 2 affected siblings presented with dilated cardiomyopathy with severe left ventricular insufficiency, woolly hair and focal palmoplantar keratosis. Both pts carried the variant of interest in compound heterozygosity with maternally inherited c.2131_2132delAG, p.S711Cfs*4. Siblings father (an obligate carrier of the variant of interest, deceased) has suffered from a MI from young age. No functional studies determining the functional impact of this variant have been conducted and published at the time of evaluation. One reputable database/clinical laboratory classified this variant as VUS. Additional clinical and functional data are needed to classify this variant with confidence. Taking together, the variant was classified as VUS-Possibly Pathogenic until more information becomes available.
Invitae RCV000816725 SCV000957246 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-09-05 criteria provided, single submitter clinical testing This sequence change replaces threonine with lysine at codon 356 of the DSP protein (p.Thr356Lys). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family affected with Carvajal syndrome (PMID: 25227139). ClinVar contains an entry for this variant (Variation ID: 199858). 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"). 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.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414775 SCV000492592 uncertain significance Primary dilated cardiomyopathy 2016-03-24 no assertion criteria provided clinical testing

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