rs267607002

chr10-110812303-C-Achr10-110812303-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001134363.3(RBM20):c.1906C>A(p.Arg636Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R636C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.74

Genes affected

RBM20 (HGNC:27424): (RNA binding motif protein 20) This gene encodes a protein that binds RNA and regulates splicing. Mutations in this gene have been associated with familial dilated cardiomyopathy. [provided by RefSeq, Apr 2014]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_001134363.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-110812304-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant 10-110812303-C-A is Pathogenic according to our data. Variant chr10-110812303-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.1906C>A	p.Arg636Ser	missense_variant	9/14	ENST00000369519.4
RBM20	XM_017016103.3	c.1741C>A	p.Arg581Ser	missense_variant	9/14
RBM20	XM_017016104.3	c.1522C>A	p.Arg508Ser	missense_variant	9/14
RBM20	XM_047425116.1	c.1522C>A	p.Arg508Ser	missense_variant	9/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.1906C>A	p.Arg636Ser	missense_variant	9/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1DD Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 17, 2023	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 636 of the RBM20 protein (p.Arg636Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 19712804, 26604136; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 270). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RBM20 protein function. Experimental studies have shown that this missense change affects RBM20 function (PMID: 22466703). This variant disrupts the p.Arg636 amino acid residue in RBM20. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19712804, 20590677, 21483645, 23861363, 24503780, 26084686). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Primary dilated cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Apr 10, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 31, 2016	The p.Arg636Ser variant in RBM20 has been reported in 3 individuals with DCM, se gregated with disease in 6 affected relatives from 2 families, and was absent fr om 960 race-matched control chromosomes (Brauch 2009). In addition, this variant has been identified by our laboratory in 1 individual with DCM and 1 individual with LVNC. In vitro functional studies provide some evidence that the p.Arg636S er variant may impact protein function (Guo 2012, Wyles 2016). However, these ty pes of assays may not accurately represent biological function. Computational pr ediction tools and conservation analysis suggest that this variant may impact th e protein, though this information is not predictive enough to determine pathoge nicity. In addition, this variant lies within exon 9, which encodes a conserved protein domain where other pathogenic variants have been reported (Brauch 2009, Li 2010). Lastly, a different disease-causing substitution has been reported at this position (p.Arg636His; Brauch 2009, Li 2010, Wells 2013, LMM data) suggesti ng that changes at this position may not be tolerated. In summary, although addi tional studies are required to fully establish its clinical significance, the p. Arg636Ser variant is likely pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 06, 2022

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies showed that the hiPSC-CMs harboring the R636S variant were less capable of maintaining their sarcomeric structure, demonstrated defective Ca2+ handling, and were more susceptible to positive chronotropic (heart rate) stress (Wyles et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID# 270); This variant is associated with the following publications: (PMID: 27363581, 22466703, 19712804, 27496873, 30871348, 30871351, 29343803, 21483645, 33019804, 34732726, 33671899, 34575212, 33188278, 34333030, 26604136) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 01, 2023

The p.R636S pathogenic mutation (also known as c.1906C>A), located in coding exon 9 of the RBM20 gene, results from a C to A substitution at nucleotide position 1906. The arginine at codon 636 is replaced by serine, an amino acid with dissimilar properties. This variant has been reported in multiple individuals with dilated cardiomyopathy (DCM) and has been shown to segregate with DCM across several families, some of which exhibited reduced penetrance (Brauch KM et al. J Am Coll Cardiol. 2009;54:930-41; Broendberg AK et al. Eur J Hum Genet. 2018 Mar;26(3):303-313; Hey TM et al. Circ Heart Fail. 2019 Mar;12(3):e005700; Stava TT et al. Eur J Prev Cardiol. 2022 Oct;29(13):1789-1799). Functional studies have indicated that this variant adversely impacts protein function (Guo W et al. Nat Med. 2012;18:766-73; Wyles SP et al. Hum Mol Genet. 2016;25:254-65). Other alterations at the same codon, p.R636C (c.1906C>T) and p.R636H (c.1907G>A), have also been reported in association with DCM (Li D et al. Clin Transl Sci. 2010;3:90-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.89	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.025	D
Vest4		0.86
MutPred		0.77		Gain of phosphorylation at R636 (P = 3e-04);
MVP		0.85
ClinPred		0.97	D
GERP RS		5.7
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267607002; hg19: chr10-112572061;