Submissions for variant NM_004415.4(DSP):c.4466T>G (p.Leu1489Arg)

gnomAD frequency: 0.00002  dbSNP: rs746782582

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000533748	SCV000641311	benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-09-27	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770245	SCV000901676	uncertain significance	Cardiomyopathy	2017-10-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780217	SCV000917306	uncertain significance	not specified	2025-04-29	criteria provided, single submitter	clinical testing	Variant summary: DSP c.4466T>G (p.Leu1489Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 249898 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4466T>G in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 465896). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000770245	SCV001355439	uncertain significance	Cardiomyopathy	2022-11-28	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with arginine at codon 1489 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 cardiovascular disorders in the literature. This variant has been identified in 5/281280 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	RCV001547456	SCV001767167	uncertain significance	not provided	2023-05-04	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function
Ambry Genetics	RCV002330885	SCV002638470	uncertain significance	Cardiovascular phenotype	2022-10-20	criteria provided, single submitter	clinical testing	The p.L1489R variant (also known as c.4466T>G), located in coding exon 23 of the DSP gene, results from a T to G substitution at nucleotide position 4466. The leucine at codon 1489 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV003999172	SCV004819125	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with arginine at codon 1489 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 cardiovascular disorders in the literature. This variant has been identified in 5/281280 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.