Submissions for variant NM_001134363.3(RBM20):c.448G>A (p.Ala150Thr)

gnomAD frequency: 0.00055  dbSNP: rs199868951

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036993	SCV000060649	likely benign	not specified	2012-12-11	criteria provided, single submitter	clinical testing	Ala150Thr in exon 2 of RBM20: This variant is not expected to have clinical sign ificance due to a lack of conservation across species, including mammals. Of not e, 14 mammals have a Threonine (Thr; this variant) at this position despite high nearby amino acid conservation. In addition, computational analyses (AlignGVGD, PolyPhen2, SIFT) do not suggest a high likelihood of impact to the protein. In addition, this variant has been identified in 3/3182 European American chromosom es from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS).
GeneDx	RCV000036993	SCV000236303	benign	not specified	2018-01-16	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Laboratory Services, Illumina	RCV000469728	SCV000360334	uncertain significance	Dilated cardiomyopathy 1DD	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.
Invitae	RCV000469728	SCV000562784	benign	Dilated cardiomyopathy 1DD	2024-01-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618530	SCV000736050	benign	Cardiovascular phenotype	2016-10-19	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770272	SCV000901704	benign	Cardiomyopathy	2021-04-23	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852627	SCV000995331	benign	Familial dilated cardiomyopathy and peripheral neuropathy	2019-06-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036993	SCV002598692	benign	not specified	2022-09-26	criteria provided, single submitter	clinical testing	Variant summary: RBM20 c.448G>A (p.Ala150Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 157176 control chromosomes in the gnomAD database, including one homozygote. The observed variant frequency is approximately 26 fold of the estimated maximal expected allele frequency for a pathogenic variant in RBM20 causing Dilated Cardiomyopathy phenotype (4.7e-05), strongly suggesting that the variant is benign. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and benign (n=5). Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV003311666	SCV004010019	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	RBM20: BP4, BS1
PreventionGenetics, part of Exact Sciences	RCV003944902	SCV004762259	benign	RBM20-related condition	2019-11-11	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000036993	SCV000280435	uncertain significance	not specified	2013-01-26	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Ala150Thr (c.448 G>A, A150T) in the RBM20 gene The variant has not been reported in association with disease. In silico analysis with PolyPhen-2 predicts the variant to be benign. The alanine at codon 150 is not conserved across species, and is in fact a threonine in some species, including mammals. Mutation taster predicts the variant to be benign. In total the variant has not been seen in 5 of ~2,579 published controls and individuals from publicly available population datasets. The variant is reported online in 3 of 1591 Caucasian individuals and 1 of 692 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of January 27th, 2013). The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. The variant is listed in dbSNP (rs199868951), which refers to the NHLBI data and data from ClinSeq. In ClinSeq it was observed in 1 of 296 individuals; this cohort approximates a general population sample (with respect to Mendelian disease). It is listed in 1000 genomes but only in reference to the dbSNP entry (as of January 27th, 2013).