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

dbSNP: rs780626687

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000590097	SCV000233575	uncertain significance	not provided	2021-06-08	criteria provided, single submitter	clinical testing	Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 199858; Landrum et al., 2016); Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 25227139, 26399581, 27535533, Rawal2021[CaseReport])
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000816725	SCV000957246	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 356 of the DSP protein (p.Thr356Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Carvajal syndrome and/or clinical features of arrhythmogenic cardiomyopathy (PMID: 25227139, 34352074). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 199858). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV001190479	SCV001357979	uncertain significance	Cardiomyopathy	2023-03-03	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with lysine at codon 356 of the DSP protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in compound heterozygosity with c.2131_2132delAG in two siblings affected with palmoplantar keratoderma, woolly hair and dilated cardiomyopathy (Carvajal syndrome), and the variant in question was inherited from the father who had myocardial infarction at a young age (PMID 25227139). This variant has been reported in another three individuals affected with DSP-related cardiomyopathy from two different families (PMID: 34352074, 36768812). This variant has also been observed in three asymptomatic individuals with imaging abnormalities involving left ventricle when screened with cardiac magnetic resonance, who were from a family with a history of arrhythmogenic ventricular cardiomyopathy and sudden cardiac death (PMID: 34317553). This variant has been identified in 1/251198 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198235	SCV001369107	uncertain significance	Keratosis palmoplantaris striata 2	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance.
Ambry Genetics	RCV002408784	SCV002723912	uncertain significance	Cardiovascular phenotype	2022-06-17	criteria provided, single submitter	clinical testing	The p.T356K variant (also known as c.1067C>A), located in coding exon 9 of the DSP gene, results from a C to A substitution at nucleotide position 1067. The threonine at codon 356 is replaced by lysine, an amino acid with similar properties. This variant was reported in two compound heterozygous siblings with a maternally inherited DSP splicing variant, dilated cardiomyopathy, woolly or sparse hair, and mild palmoplantar keratosis (Pigors M et al. Acta Derm. Venereol., 2015 Mar;95:337-40). This alteration was also reported in family members of a proband who suffered sudden cardiac death and had features of arrhythmogenic right ventricular cardiomyopathy (ARVC) on autopsy; some of the family members who had genetic testing also carried a missense alteration in JUP (Rawal AS et al. JACC Case Rep, 2021 Mar;3:438-442). This amino acid position is highly 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.
Fulgent Genetics, Fulgent Genetics	RCV002485188	SCV002782370	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	2021-08-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996641	SCV004820419	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with lysine at codon 356 of the DSP protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in compound heterozygosity with c.2131_2132delAG in two siblings affected with palmoplantar keratoderma, woolly hair and dilated cardiomyopathy (Carvajal syndrome), and the variant in question was inherited from the father who had myocardial infarction at a young age (PMID 25227139). This variant has been reported in another three individuals affected with DSP-related cardiomyopathy from two different families (PMID: 34352074, 36768812). This variant has also been observed in three asymptomatic individuals with imaging abnormalities involving left ventricle when screened with cardiac magnetic resonance, who were from a family with a history of arrhythmogenic ventricular cardiomyopathy and sudden cardiac death (PMID: 34317553). This variant has been identified in 1/251198 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414775	SCV000492592	uncertain significance	Primary dilated cardiomyopathy	2016-03-24	no assertion criteria provided	clinical testing