Submissions for variant NM_001134363.3(RBM20):c.680G>T (p.Gly227Val)

gnomAD frequency: 0.00066  dbSNP: rs202238753

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154806	SCV000204486	uncertain significance	not specified	2014-07-16	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Gly227Val varia nt in RBM20 has been identified by our laboratory in one Caucasian child with HC M. This variant has also been identified in 0.2% (5/3182) of European American c hromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu; dbSNP rs202238753). Glycine (Gly) at position 227 is not well conserved in evolu tion and one mammal (panda) carries a valine (Val) at this position, raising the possibility that this change may be tolerated. In summary, while the clinical significance of the Gly227Val variant is uncertain, these data suggest that it i s more likely to be benign.
GeneDx	RCV001528500	SCV000236326	benign	not provided	2020-06-24	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28255936, 30611920, 25351510)
Illumina Laboratory Services, Illumina	RCV000462379	SCV000360337	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.
Invitae	RCV000462379	SCV000562777	likely benign	Dilated cardiomyopathy 1DD	2024-01-30	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000590946	SCV000700142	likely benign	Primary dilated cardiomyopathy	2016-10-01	criteria provided, single submitter	research	Found in patient having exome sequencing for an unrelated indication. No known history of dilated cardiomyopathy. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Ambry Genetics	RCV000619836	SCV000735487	likely benign	Cardiovascular phenotype	2018-05-08	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770276	SCV000901708	benign	Cardiomyopathy	2019-09-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001528500	SCV002821544	benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	RBM20: BS1, BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154806	SCV004813794	likely benign	not specified	2024-02-25	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000154806	SCV000280436	uncertain significance	not specified	2013-11-13	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.Gly227Val (G227V; c.680 G>T) in the RBM20 gene. This variant has not previously been reported in individuals with DCM. The RBM20 gene is a minor cause of DCM, with mutations reported in approximately 3% of patients. This is a conservative amino acid change, resulting in the replacement of a nonpolar glycine with a nonpolar valine. Glycine at this location is 100% conserved across 8 mammalian species. The adjacent residues are not highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging” with a score of 0.976. Nonetheless, no mutations affecting nearby residues have been reported in HGMD according to GeneDx, indiacting that this region of the protein may be tolerant of change. Furthermore, the G227V variant has been seen in at least 5 individuals from >2200 individuals in publicly available population datasets. G227V is present in 5/1591 Caucasian and 0/692 African American individuals in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/). It is also listed in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP). There is no variation at this codon in 1000 Genomes.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528500	SCV001740339	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000154806	SCV001924071	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001528500	SCV001967081	likely benign	not provided		no assertion criteria provided	clinical testing