Submissions for variant NM_001134363.3(RBM20):c.3616G>A (p.Glu1206Lys)

gnomAD frequency: 0.00008  dbSNP: rs757389650

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484750	SCV000565483	uncertain significance	not provided	2020-11-03	criteria provided, single submitter	clinical testing	Observed in a patient with DCM in the published literature (Rafaat et al., 2012); Published functional studies are inconclusive in determining a damaging effect (Murayama et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 418455; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 22004663, 30547036, 29895960)
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000622264	SCV000740661	uncertain significance	Primary familial dilated cardiomyopathy	2016-09-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001243445	SCV001416603	likely benign	Dilated cardiomyopathy 1DD	2025-01-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002455912	SCV002616687	uncertain significance	Cardiovascular phenotype	2019-04-26	criteria provided, single submitter	clinical testing	The p.E1206K variant (also known as c.3616G>A), located in coding exon 14 of the RBM20 gene, results from a G to A substitution at nucleotide position 3616. The glutamic acid at codon 1206 is replaced by lysine, an amino acid with similar properties. This variant was detected in a dilated cardiomyopathy cohort; however, details were limited (Refaat MM et al. Heart Rhythm, 2012 Mar;9:390-6). One study of the equivalent variant in a mouse expression vector did not indicate a significant impact on the RBM20 properties studied (Murayama R et al. Sci Rep, 2018 Jun;8:8970). This amino acid position is well conserved in available vertebrate species; however, lysine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV001243445	SCV002778491	uncertain significance	Dilated cardiomyopathy 1DD	2021-08-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003993978	SCV004813793	uncertain significance	not specified	2024-02-08	criteria provided, single submitter	clinical testing	Variant summary: RBM20 c.3616G>A (p.Glu1206Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.7e-05 in 149856 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3616G>A has been reported in the literature in one individual affected with Dilated Cardiomyopathy, without strong evidence for causality (Refaat_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. One publication reports experimental evidence evaluating an impact on mouse protein function, however, does not allow convincing conclusions about the variant effect (Murayama_2018). The following publications have been ascertained in the context of this evaluation (PMID: 29895960, 22004663). ClinVar contains an entry for this variant (Variation ID: 418455). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004751555	SCV005345386	uncertain significance	RBM20-related disorder	2024-04-30	no assertion criteria provided	clinical testing	The RBM20 c.3616G>A variant is predicted to result in the amino acid substitution p.Glu1206Lys. This variant was reported in an individual with dilated cardiomyopathy (Refaat et al. 2012. PubMed ID: 22004663). Functional studies in a mouse homolog (p.Glu1178Lys) showed that this variant may moderately affect the protein function (Figure 6, Murayama et al. 2018. PubMed ID: 29895960). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.