ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.2719C>T (p.Arg907Cys)

gnomAD frequency: 0.00002  dbSNP: rs749051278
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000404899 SCV000464946 uncertain significance Arrhythmogenic right ventricular dysplasia 8 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV000354548 SCV000464948 uncertain significance Woolly hair-skin fragility syndrome 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV000394733 SCV000464949 uncertain significance Lethal acantholytic epidermolysis bullosa 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV000470197 SCV000543277 likely benign Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 2024-01-08 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000757185 SCV000885322 uncertain significance not specified 2018-09-28 criteria provided, single submitter clinical testing The p.Arg907Cys variant (rs749051278) has not been reported in the medical literature but is reported in ClinVar (Variation ID: 357945). This variant is found in the general population with an overall allele frequency of 0.002% (4/246106 alleles) in the Genome Aggregation Database. Another variant that affects the same codon (p.Arg907His) was reported in a patient with dilated cardiomyopathy, however, its clinical significance was not determined (Cuenca 2016). The arginine at position 907 is moderately conserved and computational analyses (SIFT, PolyPhen-2) predict that the p.Arg907Cys variant is deleterious. However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. References: Cuenca et al. Genetic basis of familial dilated cardiomyopathy patients undergoing heart transplantation. J Heart Lung Transplant. 2016 May;35(5):625-35.
Color Diagnostics, LLC DBA Color Health RCV001179332 SCV001343971 uncertain significance Cardiomyopathy 2023-05-18 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 907 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 reported for this variant. This variant has been reported in an individual affected with left ventricular noncompaction, who also carried a pathogenic truncation variant in the PKP2 gene (PMID: 32600061). This variant has been identified in 4/251328 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.
Ambry Genetics RCV002429321 SCV002744320 uncertain significance Cardiovascular phenotype 2022-03-08 criteria provided, single submitter clinical testing The p.R907C variant (also known as c.2719C>T), located in coding exon 19 of the DSP gene, results from a C to T substitution at nucleotide position 2719. The arginine at codon 907 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant co-occurred with a frameshift variant in the PKP2 gene in an individual from a left ventricular noncompaction cohort who had heart failure, arrhythmia and congenital heart defect (Hirono K et al. Circ Genom Precis Med, 2020 08;13:e002940). This variant has also been detected in individuals from a cohort not selected for the presence of cardiovascular disease; however, details were limited (Yamaguchi-Kabata Y et al. J Hum Genet, 2018 Feb;63:213-230). This amino acid position is 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.
Fulgent Genetics, Fulgent Genetics RCV002488792 SCV002800927 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 2021-10-13 criteria provided, single submitter clinical testing

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