Submissions for variant NM_004415.4(DSP):c.1A>G (p.Met1Val)

dbSNP: rs1131691557

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494668	SCV000582379	pathogenic	not provided	2015-09-24	criteria provided, single submitter	clinical testing	The c.1 A>G variant in the DSP gene has not been published previously, to our knowledge. As this variant changes the translation initiator Methionine codon, the resultant protein is described as p.Met1? using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Methionine. Although no translation initiator variants have been reported in the DSP gene, many loss-of-function variants are known to be pathogenic in this gene associated with arrhythmogenic right ventricular cardiomyopathy (Stenson et al., 2014). Based on the ACMG recommendations, c.1 A>G is interpreted as a pathogenic variant.
Color Diagnostics, LLC DBA Color Health	RCV001188452	SCV001355511	uncertain significance	Cardiomyopathy	2023-10-19	criteria provided, single submitter	clinical testing	This variant results in the loss of the translation initiation codon methionine (p.Met1?) of the DSP protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 4 individuals from a population-based cohort who had not been previously diagnosed with arrhythmogenic cardiomyopathy (PMID: 33684294). This variant has been identified in 2/233270 chromosomes in the general population by the Genome Aggregation Database (gnomAD). While loss of DSP function is a known mechanism of disease, one cannot rule out the possibility that a downstream in-frame methionine is used for alternate translation initiation and results in the production of truncated but functional DSP protein. 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	RCV003159599	SCV003867549	uncertain significance	Cardiovascular phenotype	2022-11-23	criteria provided, single submitter	clinical testing	The p.M1? variant (also known as c.1A>G) is located in coding exon 1 of the DSP gene and results from a A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This variant has been detected in individuals from a cohort not selected for the presence of cardiovascular disease; however, clinical details were limited (Carruth ED et al. Circ Genom Precis Med. 2019 11;12(11):e002579). Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however, there is an in-frame methionine 16 amino acids from the initiation site, which may result in N-terminal truncation of unknown functional significance. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.