Submissions for variant NM_004415.4(DSP):c.860A>G (p.Asn287Ser)

gnomAD frequency: 0.00003  dbSNP: rs138872423

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038114	SCV000061780	uncertain significance	not specified	2013-10-15	criteria provided, single submitter	clinical testing	The Asn287Ser variant in DSP has now been identified by our laboratory in 1 Cauc asian individual with ARVC and segregated with disease in 1 affected relative. T his variant has been identified in 1/176 of Yoruba chromosomes by the 1000 Genom es Project (dbSNP rs138872423). Computational analyses (biochemical amino acid p roperties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong s upport for or against an impact to the protein. Additional information is needed to fully assess the clinical significance of the Asn287Ser variant.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170913	SCV001333552	uncertain significance	Cardiomyopathy	2018-05-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170913	SCV001349528	uncertain significance	Cardiomyopathy	2019-10-18	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 287 of the DSP protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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 been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (Fish 2010), dilated cardiomyopathy (https://www.cardiodb.org/) and sudden death (PMID: 28472724). This variant has been identified in 1/282786 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.
Invitae	RCV001360260	SCV001556171	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 287 of the DSP protein (p.Asn287Ser). This variant is present in population databases (rs138872423, gnomAD 0.03%). This missense change has been observed in individual(s) with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy (PMID: 27532257, 28472724, 30731207). ClinVar contains an entry for this variant (Variation ID: 44977). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Asn287 amino acid residue in DSP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11841538, 25225338, 25765472). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.