Submissions for variant NM_001134363.3(RBM20):c.2989G>A (p.Val997Met)

dbSNP: rs372370653

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000810120	SCV000950309	likely benign	Dilated cardiomyopathy 1DD	2023-10-29	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256956	SCV001433490	uncertain significance	Dilated cardiomyopathy 1A	2019-10-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002440742	SCV002746329	uncertain significance	Cardiovascular phenotype	2021-08-06	criteria provided, single submitter	clinical testing	The p.V997M variant (also known as c.2989G>A), located in coding exon 11 of the RBM20 gene, results from a G to A substitution at nucleotide position 2989. The valine at codon 997 is replaced by methionine, an amino acid with highly similar properties. This variant has been detected in an individual from a hypertrophic cardiomyopathy cohort; however, clinical details were limited (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is not well conserved in available vertebrate species, and methionine 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.
Fulgent Genetics, Fulgent Genetics	RCV000810120	SCV002797588	uncertain significance	Dilated cardiomyopathy 1DD	2021-08-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317378	SCV004020799	uncertain significance	not specified	2023-06-12	criteria provided, single submitter	clinical testing	Variant summary: RBM20 c.2989G>A (p.Val997Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 156918 control chromosomes in GnomAD. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2989G>A has been reported in an individual receiving Hypertrophic cardiomyopathy genetic testing (example: van Lint_2019). This report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. This variant, arising de novo, has also been reported in an individual with non-syndromic cleft lip/palate (example: Awotoye_2022). 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: 35817949, 30847666). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, among which three classifications are uncertain significance and one is Likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.