Submissions for variant NM_004415.4(DSP):c.4022G>A (p.Arg1341His)

gnomAD frequency: 0.00006  dbSNP: rs112242645

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000686257	SCV000813767	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2023-12-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001191644	SCV001359538	uncertain significance	Cardiomyopathy	2023-06-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1341 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 individuals affected with arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, or stillbirth (PMID: 27532257,30615648, 32879264, Fish 2010, dissertation, University of Cape Town). This variant has also been identified in 17/282014 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	RCV001561798	SCV001784461	uncertain significance	not provided	2021-05-28	criteria provided, single submitter	clinical testing	Identified in a patient with DCM in published literature (Walsh et al., 2017) and in a patient with polycystic kidney disease (PKD) who developed and died of acute cardiac failure at 8 months old; exome sequencing in this patient identified a pathogenic variant in PKD1, compound heterozygous variants in JPH2, and heterozygous variants in TTN, MAP2K2, and the R1341H variant in DSP (Miura et al., 2022); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 566448; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27532257, 32879264, 27535533)
Ambry Genetics	RCV002352116	SCV002620861	uncertain significance	Cardiovascular phenotype	2023-06-06	criteria provided, single submitter	clinical testing	The p.R1341H variant (also known as c.4022G>A), located in coding exon 23 of the DSP gene, results from a G to A substitution at nucleotide position 4022. The arginine at codon 1341 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in dilated cardiomyopathy (DCM) cohorts and a stillbirth cohort; however, clinical details were limited and additional alterations were identified in some cases (Walsh R et al. Genet Med, 2017 Feb;19:192-203; Sahlin E et al. PLoS One, 2019 Jan;14:e0210017; Miura A et al. Int Heart J, 2020 Sep;61:1079-1083). 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.
Fulgent Genetics, Fulgent Genetics	RCV002485599	SCV002784627	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	2021-09-23	criteria provided, single submitter	clinical testing