Submissions for variant NM_004415.4(DSP):c.6269A>G (p.Glu2090Gly)

gnomAD frequency: 0.00002  dbSNP: rs755069593

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000641824	SCV000763474	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2023-10-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001524580	SCV001734476	uncertain significance	Cardiomyopathy	2023-05-11	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 2090 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 not been reported in individuals affected with DSP-related disorders in the literature. This variant has been identified in 6/251392 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	RCV001557006	SCV001778692	uncertain significance	not provided	2020-07-14	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Identified in patients referred for cardiomyopathy genetic testing at GeneDx, although one of these probands harbored an additional cardiogenetic variant that likely contributed to the phenotype; 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# 234989; Landrum et al., 2016)
Dept of Medical Biology, Uskudar University	RCV003318371	SCV004022078	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PM2, PP3
KardioGenetik, Herz- und Diabeteszentrum NRW	RCV003390975	SCV004101812	uncertain significance	Arrhythmogenic right ventricular dysplasia 8	2023-10-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998652	SCV004828278	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2023-05-30	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 2090 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 not been reported in individuals affected with DSP-related disorders in the literature. This variant has been identified in 6/251392 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	RCV004020712	SCV005022550	uncertain significance	Cardiovascular phenotype	2023-12-03	criteria provided, single submitter	clinical testing	The p.E2090G variant (also known as c.6269A>G), located in coding exon 24 of the DSP gene, results from an A to G substitution at nucleotide position 6269. The glutamic acid at codon 2090 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223906	SCV000280094	uncertain significance	not specified	2014-05-16	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Given the lack of case data and the type of variant, we consider this variant a variant of uncertain significance. We could find no reported cases of disease with this variant. Specifically, it is not listed in ClinVar or the ARVD mutation database. PolyPhen2 and MutationTaster both predict the variant to be disease causing with scores of 0.985 and 1.000 respectively. SIFT does not predict the variant to be disease causing, though the score (0.93) is close to the cutoff (0.95). The glutamic acid at codon 2090 is completely conserved across species. It is notable that most pathogenic variants in DSP are not missense. The variant was reported online in 2 of 60431 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of September 22nd, 2015). Specifically, the variant was observed in 2 of 33217 European individuals. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012).