Submissions for variant NM_004415.4(DSP):c.2012A>G (p.Glu671Gly)

dbSNP: rs758530970

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001042593	SCV001206285	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 671 of the DSP protein (p.Glu671Gly). This variant is present in population databases (rs758530970, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with DSP-related conditions. ClinVar contains an entry for this variant (Variation ID: 840565). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV001187059	SCV001353718	uncertain significance	Cardiomyopathy	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 671 of the DSP protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 cardiovascular disorders in the literature. This variant has not been identified 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	RCV003160289	SCV003855695	uncertain significance	Cardiovascular phenotype	2023-08-02	criteria provided, single submitter	clinical testing	The c.2012A>G (p.E671G) alteration is located in exon 15 (coding exon 15) of the DSP gene. This alteration results from a A to G substitution at nucleotide position 2012, causing the glutamic acid (E) at amino acid position 671 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987765	SCV004803590	uncertain significance	not specified	2024-01-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004004751	SCV004822049	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2024-07-10	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 671 of the DSP protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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.