10-110812310-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_001134363.3(RBM20):c.1913C>T(p.Pro638Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,397,980 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. P638Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (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:13

Conservation

PhyloP100: 7.57

Publications

26 publications found

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 Gene-Disease associations (from GenCC):

dilated cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
dilated cardiomyopathy 1DD
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hypertrophic cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

RBM20 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 13 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 chr10-110812310-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 372651.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.963

PP5

Variant 10-110812310-C-T is Pathogenic according to our data. Variant chr10-110812310-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 268.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.1913C>T	p.Pro638Leu	missense_variant	Exon 9 of 14	ENST00000369519.4	NP_001127835.2	Q5T481
RBM20	XM_017016103.3 link	c.1748C>T	p.Pro583Leu	missense_variant	Exon 9 of 14		XP_016871592.1
RBM20	XM_017016104.3 link	c.1529C>T	p.Pro510Leu	missense_variant	Exon 9 of 14		XP_016871593.1
RBM20	XM_047425116.1 link	c.1529C>T	p.Pro510Leu	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.1913C>T	p.Pro638Leu	missense_variant	Exon 9 of 14	1	NM_001134363.3	ENSP00000358532.3		Q5T481
RBM20	ENST00000718239.1 link	c.1913C>T	p.Pro638Leu	missense_variant	Exon 9 of 14			ENSP00000520684.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1397980

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

689358

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31576

American (AMR)

AF:

0.00

AC:

AN:

35660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25154

East Asian (EAS)

AF:

0.00

AC:

AN:

35702

South Asian (SAS)

AF:

0.00

AC:

AN:

79190

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48714

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1078310

Other (OTH)

AF:

0.00

AC:

AN:

57980

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1DD

Pathogenic:6

Sep 01, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 19, 2025

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG criteria used: PS3_supporting, PS4, PM2, PP1_strong and PP3. -

Mar 22, 2022

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000268, PMID:19712804). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000202063). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.81>=0.6). A missense variant is a common mechanism associated with Cardiomyopathy, dilated, 1DD . It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Aug 03, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 638 of the RBM20 protein (p.Pro638Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (DCM) (PMID: 19712804, 22004663). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 268). 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: 22466703). For these reasons, this variant has been classified as Pathogenic. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 26, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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; Published functional studies demonstrate a damaging effect as a cell-based splice reporter assay showed complete loss of protein function (Guo et al., 2012) and human cardiac tissue cell culture showed an abnormal cytoplasmic localization of the protein (Gaertner et al., 2020); This variant is associated with the following publications: (PMID: 24584570, 24503780, 24033266, 22004663, 27532257, 29367541, 28798025, 30547036, 20590677, 32969603, 29650543, 30871351, 30871348, 29253866, 32840935, 30847666, 32746448, 19712804, 22466703, 31737537) -

Dilated cardiomyopathy 1S

Pathogenic:1

May 01, 2016

Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

RBM20-related disorder

Pathogenic:1

Jun 12, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The RBM20 c.1913C>T variant is predicted to result in the amino acid substitution p.Pro638Leu. This variant has been reported in many individuals with dilated cardiomyopathy and has been shown to segregate with disease in multiple large families (see for example, Brauch et al 2009. PubMed ID: 19712804; Gaertner A et al 2020. PubMed ID: 32840935; Long PA et al 2017. PubMed ID: 29367541). In addition, functional analysis in vitro, suggests that the p.Pro638Leu variant is deleterious (Guo W et al 2012. PubMed ID: 22466703; Gaertner A et al 2020. PubMed ID: 32840935). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. This variant is interpreted as pathogenic. -

Dilated cardiomyopathy 1A

Pathogenic:1

May 04, 2020

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary dilated cardiomyopathy

Pathogenic:1

Dec 16, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Pro638Leu variant in RBM20 has been reported in 3 families with DCM, segre gated with disease in >10 affected individuals (including 2 affected obligate ca rriers) and was absent from 2160 control chromosomes (Brauch 2009, Refaat 2012) and other large population studies. Additionally, this variant has been identifi ed by our laboratory in 2 individuals with DCM and LV dilation/dysfunction, 1 in dividual with atypical ARVC, and segregated with disease in 2 affected relatives . In vitro studies suggest that the p.Pro638Leu variant may impact protein funct ion (Guo 2012). Proline (Pro) at position 638 is highly conserved in mammals and evolutionarily distant species and lies within a conserved protein domain in wh ich other pathogenic variants have been reported (Brauch 2009, Li 2010). In summ ary, this variant meets our criteria to be classified as pathogenic for DCM in a n autosomal dominant manner (http://www.partners.org/personalizedmedicine/LMM) based upon segregation studies, absence from controls, and functional evidence. -

Cardiovascular phenotype

Pathogenic:1

Jul 01, 2021

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P638L pathogenic mutation (also known as c.1913C>T), located in coding exon 9 of the RBM20 gene, results from a C to T substitution at nucleotide position 1913. The proline at codon 638 is replaced by leucine, an amino acid with similar properties. This alteration has been detected in individuals with dilated cardiomyopathy (DCM), and has been reported to segregate with disease in multiple families (Brauch KM et al. J Am Coll Cardiol. 2009 Sep;54:930-41; Refaat MM et al. Heart Rhythm. 2012;9:390-6; Pugh TJ et al. Genet Med. 2014;16:601-8; Long PA et al. J Cardiovasc Dev Dis, 2017 Aug;4; Klauke B et al. PLoS One, 2017 Dec;12:e0189489; Gaertner A et al. Hum Mutat, 2020 11;41:1931-1943). In addition, this alteration has been noted as occurring in the RS-rich hot spot region, and studies have suggested this alteration results in cytoplasmic mislocalization and altered protein function (Guo W et al. Nat Med. 2012;18:766-73; Gaertner A et al. Hum Mutat, 2020 11;41:1931-1943). 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

0.68

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.96

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

0.86

PhyloP100

7.6

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-6.2

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Vest4

0.86

MutPred

0.71

Loss of glycosylation at P638 (P = 0.0459);

MVP

0.88

ClinPred

1.0

GERP RS

5.7

gMVP

0.69

Mutation Taster

=18/82

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over