ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.2799G>C (p.Leu933Phe)

gnomAD frequency: 0.00009  dbSNP: rs372922674
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001705402 SCV000321566 uncertain significance not provided 2021-06-30 criteria provided, single submitter clinical testing Observed in an individual with ARVC and classified as a variant of unknown pathogenicity in the published literature (Walsh et al., 2017; Ye et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID 265104; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26582918, 27532257, 27535533, 31402444)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000255568 SCV000711382 uncertain significance not specified 2017-01-11 criteria provided, single submitter clinical testing The p.Leu933Phe variant in DSP has been reported in 1 individual with ARVC (Wals h 2016). This variant has also been reported in ClinVar (Variation ID 265104). T his variant has been identified in 8/65790 European chromosomes by the Exome Agg regation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs372922674). C omputational prediction tools and conservation analysis do not provide strong su pport for or against an impact to the protein. In summary, the clinical signific ance of the p.Leu933Phe variant is uncertain.
Ambry Genetics RCV000620068 SCV000737482 uncertain significance Cardiovascular phenotype 2023-07-25 criteria provided, single submitter clinical testing The p.L933F variant (also known as c.2799G>C), located in coding exon 20 of the DSP gene, results from a G to C substitution at nucleotide position 2799. The leucine at codon 933 is replaced by phenylalanine, an amino acid with highly similar properties. This variant was identified in a cohort that underwent genetic testing for arrhythmogenic right ventricular cardiomyopathy; however, clinical details were limited (Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is well 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 RCV000699886 SCV000828616 likely benign Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 2025-01-26 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001171091 SCV001333766 uncertain significance Cardiomyopathy 2019-01-08 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001171091 SCV001351719 uncertain significance Cardiomyopathy 2023-02-23 criteria provided, single submitter clinical testing This missense variant replaces leucine with phenylalanine at codon 933 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 been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 27532257). This variant has been identified in 21/282260 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.
Fulgent Genetics, Fulgent Genetics RCV002487168 SCV002780865 uncertain significance Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8; Lethal acantholytic epidermolysis bullosa; Woolly hair-skin fragility syndrome; Keratosis palmoplantaris striata 2; Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis 2021-11-01 criteria provided, single submitter clinical testing

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