Submissions for variant NM_001134363.3(RBM20):c.1748G>A (p.Gly583Asp)

gnomAD frequency: 0.00002  dbSNP: rs767827357

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183894	SCV000236376	uncertain significance	not provided	2023-02-16	criteria provided, single submitter	clinical testing	Identified in a teenager with early onset atrial fibrillation who harbors multiple cardiogenetic variants (Goodyer et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31638414)
Illumina Laboratory Services, Illumina	RCV000551578	SCV000360354	uncertain significance	Dilated cardiomyopathy 1DD	2018-01-12	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	RCV000551578	SCV000648356	likely benign	Dilated cardiomyopathy 1DD	2024-05-29	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170724	SCV001333327	uncertain significance	Cardiomyopathy	2018-04-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408815	SCV002716104	uncertain significance	Cardiovascular phenotype	2021-07-12	criteria provided, single submitter	clinical testing	The p.G583D variant (also known as c.1748G>A), located in coding exon 7 of the RBM20 gene, results from a G to A substitution at nucleotide position 1748. The glycine at codon 583 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and aspartic acid is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000183894	SCV000925210	uncertain significance	not provided	2017-04-25	no assertion criteria provided	provider interpretation	Found in a 16 year-old male with lone atrial fibrillation and a family history of heart failure and arrhythmias. Testing was done at Invitae. p.Gly583Asp (c.1748G>A) in exon 7 of the RBM20 gene (NM_001134363.2) Chromosome position: 10:112559624 G / A The RBM20 gene is associated with autosomal dominant dilated cardiomyopathy (DCM) (MedGen UID: 416441). Based on the information reviewed below, including that Aspartic Acid is accepted as the default amino acid at this codon in at least 21 species, we classify this as a Variant of Uncertain Significance, Probably Benign, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. This variant has not previously been reported in the literature in association with disease. This is a nonconservative amino acid change, resulting in the replacement of a nonpolar Glycine with a negatively-charged Aspartic Acid. Glycine at this location is poorly conserved across ~100 vertebrate species for which we have data, and Aspartic Acid is in fact the default amino acid in at least 21 species. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). There is no Likely Pathogenic or Pathogenic missense variant currently listed in ClinVar at a nearby residue (+/- 10), which may indicate that this part of the protein is tolerant of change. This variant was reported in 8 individuals in the gnomAD database, which includes ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. However, there are variant calls at this site for only 91,833 individuals, indicating that it may be a low-quality site. Specifically, the variant was observed in 3 Latino individuals (for the highest allele frequency: 0.012%), and 5 non-Finnish Europeans. Out patient’s ancestry is Latino. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases.