Submissions for variant NM_004415.4(DSP):c.652A>G (p.Ile218Val)

dbSNP: rs987363401

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481934	SCV000571751	uncertain significance	not provided	2017-04-10	criteria provided, single submitter	clinical testing	The I218V variant of uncertain significance in the DSP gene has not been published as a pathogenic or benign variantto our knowledge. This variant was not observed in approximately 6,500 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in thesepopulations. The I218V variant is a conservative amino acid substitution, which is not likely to impact secondaryprotein structure as these residues share similar properties. Furthermore, this substitution occurs at a position whereamino acids with similar properties to Isoleucine are tolerated across species, and V218 is tolerated in at least onespecies. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the proteinstructure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Color Diagnostics, LLC DBA Color Health	RCV001177924	SCV001342237	uncertain significance	Cardiomyopathy	2023-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 218 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/251446 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.
All of Us Research Program, National Institutes of Health	RCV004003372	SCV004816681	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2023-12-07	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 218 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/251446 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.