rs267607004

Positions:

• chr10-110812304-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_001134363.3(RBM20):​c.1907G>A​(p.Arg636His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 9.60

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 14 ACMG points.

• PM1: In a region_of_interest RS (size 27) in uniprot entity RBM20_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_001134363.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842
• PP5: Variant 10-110812304-G-A is Pathogenic according to our data. 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. Variant chr10-110812304-G-A is described in Lovd as [Likely_pathogenic]. Variant chr10-110812304-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.1907G>A	p.Arg636His	missense_variant	9/14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.1742G>A	p.Arg581His	missense_variant	9/14		XP_016871592.1
RBM20	XM_017016104.3	c.1523G>A	p.Arg508His	missense_variant	9/14		XP_016871593.1
RBM20	XM_047425116.1	c.1523G>A	p.Arg508His	missense_variant	9/14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.1907G>A	p.Arg636His	missense_variant	9/14	1	NM_001134363.3	ENSP00000358532.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74330

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1DD Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 636 of the RBM20 protein (p.Arg636His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy (DCM) (PMID: 19712804, 20590677, 23861363, 24503780, 26084686). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 271). 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. 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: 20590677, 21483645). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2010	- -
Pathogenic, no assertion criteria provided	clinical testing	KTest Genetics, KTest	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Apr 06, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust	Jul 10, 2024	PM1_Mod PM6_Supp PP1_Str PS4_Str -

Primary dilated cardiomyopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Feb 25, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 04, 2015	The p.Arg636His variant in RBM20 has been reported in 5 individuals with DCM, se gregated with disease in >20 affected relatives (including multiple obligate car riers), and was absent from over 2000 control chromosomes (Brauch 2009, Li 2010, Wells 2013, LMM unpublished data). In summary, this variant meets our criteria to be classified as pathogenic for DCM in an autosomal dominant manner based upo n segregation studies and absence from controls. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Nov 08, 2022	The RBM20 c.1907G>A variant is classified as Pathogenic (PS4, PP1_Strong, PM1, PM2, PP3) The RBM20 c.1907G>A variant is a single nucleotide change in exon 9/14 of the RBM20 gene, which is predicted to change the amino acid arginine at position 636 in the protein, to histidine. The variant has been reported in >15 probands with a clinical presentation of Dilated Cardiomyopathy (PMID#19712804, 20590677, 31514951, 30871348, ClinVar) (PS4) and is reported to co-segregate with disease in 7 meioses (PMID#23861363) (PP1_strong). This variant is located in the RBM20 enrichment region for variants associated with cardiomyopathy (exon 9) and different changes to this same amino acid are also reported as disease causing (PM1). The variant is rare in population databases (gnomAD allele frequency = 0.0013%; 2 het and 0 hom) (PM2) is reported in dbSNP (rs267607004), is reported as disease causing in the HGMD database (CM095006) and is reported as pathogenic/likely pathogenic by other diagnostic laboratories (ClinVar #271) Computational predictions support a deleterious effect on the gene or gene product (PP3). -

Primary familial dilated cardiomyopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Apr 29, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 17, 2022	Variant summary: RBM20 c.1907G>A (p.Arg636His) results in a non-conservative amino acid change located in the arginine/serine-rich region (RS) domain of the encoded protein sequence (Filippello_2013). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 154548 control chromosomes., c.1907G>A, has been reported in the literature in multiple individuals affected with Dilated Cardiomyopathy and was shown to segregate with disease in a large DCM family (example Wells_2013, Brauch_2009, Akinrinade_2015 and Garcia-Molina_2019 etc.). These data indicate that the variant is very likely to be associated with disease. Additionally, other variants affecting the same codon have also been reported in association with DCM (p.Arg636Cys, p.Arg636Ser), strongly suggesting the importance of the codon. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=6) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	May 04, 2022	PS4, PP3, PM1, PM5 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24503780, 27532257, 30871348, 26084686, 23861363, 20590677, 19712804, 25448463, 30471092, 30871351, 30972196, 31514951, 33906374, 34088380, 32851336, 33019804) -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Nov 28, 2018

- -

RBM20-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 17, 2024

The RBM20 c.1907G>A variant is predicted to result in the amino acid substitution p.Arg636His. This variant has been reported to be causative for dilated cardiomyopathy and found to segregate in multiple families (Brauch et al. 2009. PubMed ID: 19712804; Li et al. 2010. PubMed ID: 20590677; Table S1, Gigli et al. 2019. PubMed ID: 31514951). Functional studies showed that this variant results in aberrant subcellular localization (rat ortholog p.Arg639His in Figure 8, Zhang et al. 2023. PubMed ID: 37219949). This variant has not been reported in a large population database, indicating this variant is rare. Different nucleotide substitutions affecting the same amino acid (p.Arg636Ser, p.Arg636Cys, p.Arg636Leu) have been reported in individuals with dilated cardiomyopathy (Human Gene Mutation Database). Taken together, the c.1907G>A (p.Arg636His) variant is interpreted as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 22, 2023

The p.R636H pathogenic mutation (also known as c.1907G>A), located in coding exon 9 of the RBM20 gene, results from a G to A substitution at nucleotide position 1907. The arginine at codon 636 is replaced by histidine, an amino acid with highly similar properties. This mutation has been reported in several individuals with dilated cardiomyopathy (DCM), and has been shown to segregate with disease in multi-generational families with DCM (Brauch KM et al. J Am Coll Cardiol. 2009;54:930-41; Li D et al. Clin Transl Sci. 2010;3:90-7; Wells QS et al. Circ Cardiovasc Genet. 2013;6:317-26). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, other alterations at this codon (p.R636S and p.R636C) have also been reported in association with DCM (Brauch KM et al. J Am Coll Cardiol. 2009;54:930-41;Li D et al. Clin Transl Sci. 2010;3:90-7). 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	0.58
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Pathogenic	0.97	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Vest4		0.57
MutPred		0.72		Loss of methylation at R636 (P = 0.0163);
MVP		0.94
ClinPred		0.99	D
GERP RS		5.7
gMVP		0.65

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: rs267607004; hg19: chr10-112572062;