10-110812303-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_001134363.3(RBM20):c.1906C>T(p.Arg636Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000194 in 1,549,338 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R636H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4U:1

Conservation

PhyloP100: 5.74

Variant links:

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]

RBM20 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-110812304-G-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.88

PP5

Variant 10-110812303-C-T is Pathogenic according to our data. Variant chr10-110812303-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 43980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3 link	c.1906C>T	p.Arg636Cys	missense_variant	Exon 9 of 14	ENST00000369519.4	NP_001127835.2	Q5T481
RBM20	XM_017016103.3 link	c.1741C>T	p.Arg581Cys	missense_variant	Exon 9 of 14		XP_016871592.1
RBM20	XM_017016104.3 link	c.1522C>T	p.Arg508Cys	missense_variant	Exon 9 of 14		XP_016871593.1
RBM20	XM_047425116.1 link	c.1522C>T	p.Arg508Cys	missense_variant	Exon 9 of 14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4 link	c.1906C>T	p.Arg636Cys	missense_variant	Exon 9 of 14	1	NM_001134363.3	ENSP00000358532.3		Q5T481

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1397146

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

688808

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000186

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74330

show subpopulations

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1DD

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 07, 2025	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 636 of the RBM20 protein (p.Arg636Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of RBM20-related conditions and/or dilated cardiomyopathy (PMID: 20590677, 21483645, 31317183, 31737537; internal data). ClinVar contains an entry for this variant (Variation ID: 43980). Invitae Evidence 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 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: 30262925). 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, 22466703, 23861363). 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. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 22, 2021

Reported in ClinVar (ClinVar Variant ID# 43980; Landrum et al., 2016); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a damaging effect as this variant may result in a protein trafficking defect (Brodehl et al., 2019); This variant is associated with the following publications: (PMID: 30262925, 21483645, 19712804, 30547036, 32160020, 20590677, 29961767, 30871351, 31317183, 31737537) -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2023

The p.R636C pathogenic mutation (also known as c.1906C>T), located in coding exon 9 of the RBM20 gene, results from a C to T substitution at nucleotide position 1906. The arginine at codon 636 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in probands with dilated cardiomyopathy (DCM), has segregated with disease in two affected individuals in one family, and occurs in a RS-rich hot spot region (Li D et al. Clin Transl Sci. 2010;3:90-7; Minoche AE et al. Genet. Med.. 2019 03;21(3):650-662). One in vitro study reported this alteration to result in abnormal protein localization (Brodehl A et al. Genet. Med. 2018 Sep). Based on internal structural analysis, this variant is predicted to be structurally disruptive (Jang S et al. Nucleic Acids Res. 2019 May;47(9):4663-4683; Ambry internal data). In addition, other alterations involving the same amino acid, p.R636H (c.1907G>A) and p.R636S (c.1906C>A), have been detected in families with DCM (Brauch KM et al. J Am Coll Cardiol. 2009;54:930-41). 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. -

not specified

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 29, 2017

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg636Cys variant in RBM20 has been identified in 2 individuals with DCM and segregated w ith disease in 1 affected relative (Li 2010, LMM data). This variant was absent from large population databases; however, this frequency information may be unre liable as metrics indicate poor data quality at this position. This variant has also been reported in ClinVar (Variation ID: 43980). This variant lies within ex on 9, which encodes a conserved protein domain where other pathogenic variants h ave been reported (Brauch 2009, Li 2010). In addition, different disease-causing variants involving this amino acid position (p.Arg636His; p.Arg636Ser) have bee n reported in affected individuals, suggesting that the p.Arg636Cys variant may not be tolerated. In summary, while there is some suspicion for a pathogenic rol e, the clinical significance of the p.Arg636Cys variant is uncertain. ACMG/AMP C riteria applied: PS4_Supporting, PM1, PM5. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.95

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.88

MetaSVM

Pathogenic

0.97

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-4.6

REVEL

Pathogenic

0.68

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Vest4

0.68

MutPred

0.56

Loss of MoRF binding (P = 0.0154);

MVP

0.88

ClinPred

0.99

GERP RS

5.7

gMVP

0.71

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over