Submissions for variant NM_004415.4(DSP):c.2684A>G (p.Tyr895Cys)

gnomAD frequency: 0.00004  dbSNP: rs367752002

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000171390	SCV000197806	uncertain significance	not provided	2022-06-23	criteria provided, single submitter	clinical testing	The p.Tyr895Cys variant in DSP has been seen in 2 individuals with Arrhythmogenic right ventricular cardiomyopathy (Caforio 2020 PMID: 32114801, LMM data). It has also been identified in 0.08% (6/7212) of Other and 0.059% (18/30616) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 163257). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting, BS1.
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre	RCV000171390	SCV000221587	likely pathogenic	not provided		criteria provided, single submitter	research
GeneDx	RCV000171390	SCV000233596	uncertain significance	not provided	2021-02-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#163257; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26112015, 31110529)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000171390	SCV000603391	uncertain significance	not provided	2017-05-17	criteria provided, single submitter	clinical testing	The p.Tyr895Cys variant (rs367752002) has not been reported in the medical literature nor has it been previously identified in our laboratory; however, it is listed in the ClinVar database as a variant of uncertain significance (Variation ID: 163257). It is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.0004% (identified in 41 out of 277,050 chromosomes). The tyrosine at codon 895 is moderately conserved considering 12 species (Alamut software v2.9), and computational analyses return mixed results regarding the effect of this variant on DSP protein structure/function (SIFT: tolerated, PolyPhen2: possibly damaging, and Mutation Taster: disease causing). Thus, based on the available information, the clinical significance of the p.Tyr895Cys variant cannot be determined with certainty.
Color Diagnostics, LLC DBA Color Health	RCV000777747	SCV000913709	uncertain significance	Cardiomyopathy	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 895 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: 32114801) and in an individual affected with hypertrophic cardiomyopathy (PMID: 31110529). This variant has also been identified in 44/282708 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	RCV001243440	SCV001416597	benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2023-12-23	criteria provided, single submitter	clinical testing
Genetics and Genomics Program, Sidra Medicine	RCV001293120	SCV001434110	uncertain significance	Primary dilated cardiomyopathy		criteria provided, single submitter	research
Ambry Genetics	RCV002433646	SCV002745278	likely benign	Cardiovascular phenotype	2022-06-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV002478423	SCV002779765	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	2021-10-02	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998198	SCV004822061	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 895 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: 32114801) and in an individual affected with hypertrophic cardiomyopathy (PMID: 31110529). This variant has also been identified in 44/282708 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.
Blueprint Genetics	RCV000157192	SCV000206916	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2014-09-18	no assertion criteria provided	clinical testing