ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.8117A>T (p.Lys2706Met)

gnomAD frequency: 0.00004  dbSNP: rs537588390
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587494 SCV000698449 uncertain significance not provided 2017-01-23 criteria provided, single submitter clinical testing Variant summary: The DSP c.8117A>T (p.Lys2706Met) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a damaging outcome for this variant. This variant was found in 5/121266 control chromosomes at a frequency of 0.0000412, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic DSP variant (0.000025), suggesting this variant is possibly a benign polymorphism. However, due to limit number of occurrences in ExAC controls, benign classifcation of this variant can not be unequivocally established. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as VUS.
Color Diagnostics, LLC DBA Color Health RCV000772488 SCV000905667 uncertain significance Cardiomyopathy 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces lysine with methionine at codon 2706 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 studies have not been performed for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 25351510) and in two brothers affected with dilated cardiomyopathy who also carried a pathogenic variant in the LMNA gene (PMID: 28790152). This variant has been identified in 10/282828 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000804647 SCV000944564 likely benign Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 2024-01-27 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002497237 SCV002812182 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 2021-07-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV003159999 SCV003904494 uncertain significance Cardiovascular phenotype 2022-11-09 criteria provided, single submitter clinical testing The p.K2706M variant (also known as c.8117A>T), located in coding exon 24 of the DSP gene, results from an A to T substitution at nucleotide position 8117. The lysine at codon 2706 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301). Additionally, this alteration was detected in a family with dilated cardiomyopathy (DCM), where an additional alteration in LMNA was identified (Hoorntje ET et al. Circ Cardiovasc Genet, 2017 Aug;10:[ePub ahead of print]). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Mayo Clinic Laboratories, Mayo Clinic RCV000587494 SCV004227191 uncertain significance not provided 2022-07-12 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004002439 SCV004821610 uncertain significance Arrhythmogenic cardiomyopathy with wooly hair and keratoderma 2024-01-11 criteria provided, single submitter clinical testing This missense variant replaces lysine with methionine at codon 2706 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 studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 10/282828 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.
GeneDx RCV000587494 SCV005325746 uncertain significance not provided 2023-12-19 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in affected individuals within a family who also harbored a pathogenic LMNA variant; however, the DSP variant showed incomplete segregation with disease (PMID: 28790152); This variant is associated with the following publications: (PMID: 28790152)
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital RCV000678706 SCV000804870 uncertain significance Primary dilated cardiomyopathy 2017-08-29 no assertion criteria provided clinical testing

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