Submissions for variant NM_004415.4(DSP):c.4175G>A (p.Arg1392Gln)

gnomAD frequency: 0.00009  dbSNP: rs201736018

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001704862	SCV000233614	likely benign	not provided	2024-03-19	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000815172	SCV000955619	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2025-01-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001180303	SCV001345198	uncertain significance	Cardiomyopathy	2023-05-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1392 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 two individuals affected with dilated cardiomyopathy (PMID: 26406308, 31983221). This variant has also been identified in 23/282676 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000181320	SCV001467873	likely benign	not specified	2020-12-07	criteria provided, single submitter	clinical testing	Variant summary: DSP c.4175G>A (p.Arg1392Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 251276 control chromosomes. The observed variant frequency is approximately 8.4-fold the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. c.4175G>A has been reported in the literature in individuals affected with dilated cardiomyopathy (e.g. Marston_2015, Mazzarotto_2020), but also in healthy controls (e.g. Mazzarotto_2020). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001704862	SCV001473469	uncertain significance	not provided	2020-04-14	criteria provided, single submitter	clinical testing	The DSP c.4175G>A; p.Arg1392Gln variant (rs201736018) is reported in the literature in an individual affected with dilated cardiomyopathy (Marston 2015). This variant is reported in ClinVar (Variation ID: 199883), and is found in the general population with an overall allele frequency of 0.0081% (23/282676 alleles) in the Genome Aggregation Database. The arginine at codon 1392 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Arg1392Gln variant is uncertain at this time. References: Marston et al. OBSCN Mutations Associated with Dilated Cardiomyopathy and Haploinsufficiency. PLoS One. 2015 Sep 25;10(9):e0138568.
Ambry Genetics	RCV002326981	SCV002630320	uncertain significance	Cardiovascular phenotype	2024-11-25	criteria provided, single submitter	clinical testing	The p.R1392Q variant (also known as c.4175G>A), located in coding exon 23 of the DSP gene, results from a G to A substitution at nucleotide position 4175. The arginine at codon 1392 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in dilated cardiomyopathy (DCM) cohorts; however, clinical details were limited (Marston S et al. PLoS ONE, 2015 Sep;10:e0138568; Mazzarotto F et al. Circulation, 2020 02;141:387-398). This amino acid position is well 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001180303	SCV003838434	uncertain significance	Cardiomyopathy	2023-06-26	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001704862	SCV004234414	uncertain significance	not provided	2023-05-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996650	SCV004822091	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1392 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 two individuals affected with dilated cardiomyopathy (PMID: 26406308, 31983221). This variant has also been identified in 23/282676 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.