Submissions for variant NM_004415.4(DSP):c.3338G>A (p.Arg1113Gln)

gnomAD frequency: 0.00006  dbSNP: rs768455823

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000531336	SCV000641305	benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2023-09-11	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001165020	SCV001327186	uncertain significance	Lethal acantholytic epidermolysis bullosa	2018-04-20	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	RCV001165021	SCV001327187	uncertain significance	Arrhythmogenic right ventricular dysplasia 8	2018-04-20	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	RCV001165022	SCV001327188	uncertain significance	Woolly hair-skin fragility syndrome	2018-04-20	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.
Color Diagnostics, LLC DBA Color Health	RCV001177349	SCV001341546	likely benign	Cardiomyopathy	2020-09-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002323974	SCV002605694	likely benign	Cardiovascular phenotype	2021-11-05	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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786120	SCV000924781	uncertain significance	not provided	2017-03-29	no assertion criteria provided	provider interpretation	Given that there are no cases reported in the literature with this variant and the limited evidence that missense variation is a mechanism of pathogenicity in this gene, we consider this variant a variant of uncertain signifiance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). There is no case data available on this variant. This variant is not present in ClinVar. It is currently unclear what role, if any, missense variation in DSP has in cardiomyopathy: Kapplinger et al. (2011) from Michael Ackerman’s group have reported a significant yield of rare missense variants in the ARVC genes of presumably healthy controls from various ethnicities. According to their data, 16% of 427 controls hosted missense variants similar to the 21% yield in 175 Dutch and U.S. ARVC cases. Walsh et al (2016) found that truncating DSP variants were enriched in cases of DCM over ExAC controls with odds ration of 41.0. There was not significant enrichment of DSP missense variants in DCM cases. DSP truncating variants were also enriched in ARVC cases vs. ExAC controls with odds ratio of 89.9. DSP missense variants were only slightly enriched in cases of ARVC vs. ExAC controls with odds ratio of 2.1. This is a reminder that missense variants of unknown significance in ARVC-related genes need to be interpreted with caution. This variant is located outside of the "hot spot" of pathogenic variation in DSP (amino acids 250-604). The arginine at codon 1113 is conserved across species, as are neighboring amino acids. The variant was reported online in 11 of 122,391 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 9 of 8,607 individuals of East Asian descent (MAF=0.05%) and 2 of 15,354 individuals of South Asian descent. The phenotype of those individuals is not publicly available. Additional variants at codon 1113 are present in gnomAD: p.Arg1113Gly is present in 1 out of 12,763 individuals of Latino descent and p.Arg1113Arg (c.3338G>T) is present in 1 out of 7,554 individuals of African descent. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012).