Submissions for variant NM_004415.4(DSP):c.197A>T (p.Gln66Leu)

gnomAD frequency: 0.00001  dbSNP: rs794728152

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181376	SCV000233677	uncertain significance	not provided	2014-09-04	criteria provided, single submitter	clinical testing	p.Gln66Leu (CAG>CTG): c.197 A>T in exon 2 of the DSP gene (NM_004415.2). The Q66L variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The Q66L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Q66L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense mutations in nearby residues have not been reported, indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Ambry Genetics	RCV002415769	SCV002718303	uncertain significance	Cardiovascular phenotype	2021-09-24	criteria provided, single submitter	clinical testing	The p.Q66L variant (also known as c.197A>T), located in coding exon 2 of the DSP gene, results from an A to T substitution at nucleotide position 197. The glutamine at codon 66 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is highly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002516833	SCV003010876	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2022-09-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004806172	SCV005428772	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2024-04-25	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with leucine at codon 66 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 not been reported in individuals affected with DSP-related disorders in the literature. This variant has been identified in 1/31412 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.