Submissions for variant NM_004415.4(DSP):c.8467C>G (p.Pro2823Ala)

gnomAD frequency: 0.00020  dbSNP: rs142717240

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038106	SCV000061772	likely benign	not specified	2018-12-31	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Eurofins Ntd Llc (ga)	RCV000587297	SCV000228148	uncertain significance	not provided	2015-01-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000587297	SCV000233650	uncertain significance	not provided	2024-03-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in association with hypertrophic cardiomyopathy (HCM), sudden death and arrhythmogenic right ventricular cardiomyopathy (ARVC); however, clinical details and family history information were not available in all cases (PMID: 31737537, 25351510, 36964991; Bonaventura et al., 2018); This variant is associated with the following publications: (PMID: 24448499, 31737537, 25351510, 36964991, 29590070)
Illumina Laboratory Services, Illumina	RCV000302977	SCV000465259	uncertain significance	Arrhythmogenic right ventricular dysplasia 8	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000357526	SCV000465260	uncertain significance	Woolly hair-skin fragility syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000405429	SCV000465261	uncertain significance	Lethal acantholytic epidermolysis bullosa	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000477077	SCV000543252	benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2025-01-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038106	SCV000698452	likely benign	not specified	2024-07-01	criteria provided, single submitter	clinical testing	Variant summary: DSP c.8467C>G (p.Pro2823Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 248538 control chromosomes. The observed variant frequency is approximately 32 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. c.8467C>G has been reported in the literature in one individual affected with arrhythmogenic right ventricular cardiomyopathy and Icelanders from general population (Marschall_2019, Jensson_2023). This report does not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24448499, 31737537). The following publications have been ascertained in the context of this evaluation (PMID: 24448499, 31737537, 37937776). ClinVar contains an entry for this variant (Variation ID: 44969). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV000619198	SCV000736855	likely benign	Cardiovascular phenotype	2021-09-07	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.
Color Diagnostics, LLC DBA Color Health	RCV000771367	SCV000903662	likely benign	Cardiomyopathy	2019-12-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587297	SCV002048739	uncertain significance	not provided	2021-03-02	criteria provided, single submitter	clinical testing	The DSP c.8467C>G; p.Pro2823Ala variant (rs142717240) is reported in the literature in a cohort of individuals affected with hypertrophic cardiomyopathy, although it was not demonstrated to be disease-causing (Lopes 2015). This variant is found in the non-Finnish European population with an overall allele frequency of 0.05% (68/127642 alleles) in the Genome Aggregation Database. The proline at codon 2823 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.351). Due to limited information, the clinical significance of the p.Pro2823Ala variant is uncertain at this time. References: Lopes LR et al. Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. Heart. 2015 Feb;101(4):294-301.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000771367	SCV004240546	likely benign	Cardiomyopathy	2023-05-16	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000302977	SCV005399558	likely benign	Arrhythmogenic right ventricular dysplasia 8	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as likely benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of autosomal dominant arrhythmogenic right ventricular dysplasia 8 (MIM#607450), with 86 heterozygotes in gnomAD v2. (B) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
All of Us Research Program, National Institutes of Health	RCV004803132	SCV005424642	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2024-09-25	criteria provided, single submitter	clinical testing