10-110812310-C-T

Position:

• chr10-110812310-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_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 (★★). Synonymous variant affecting the same amino acid position (i.e. P638P) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 7.57

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 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
• 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 id is 268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-110812310-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.1913C>T	p.Pro638Leu	missense_variant	9/14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.1748C>T	p.Pro583Leu	missense_variant	9/14		XP_016871592.1
RBM20	XM_017016104.3	c.1529C>T	p.Pro510Leu	missense_variant	9/14		XP_016871593.1
RBM20	XM_047425116.1	c.1529C>T	p.Pro510Leu	missense_variant	9/14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.1913C>T	p.Pro638Leu	missense_variant	9/14	1	NM_001134363.3	ENSP00000358532.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1397980 Hom.: 0 Cov.: 32 AF XY: 0.00000290 AC XY: 2 AN XY: 689358

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: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1DD Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 03, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2023	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) and dilated cardiomyopathy (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). 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). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	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. -

Dilated cardiomyopathy 1S Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

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

May 01, 2016

- -

RBM20-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 12, 2023

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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 26, 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; 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 1A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

May 04, 2020

- -

Primary dilated cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 16, 2014

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 01, 2021

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	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.86	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Vest4		0.86
MutPred		0.71		Loss of glycosylation at P638 (P = 0.0459);
MVP		0.88
ClinPred		1.0	D
GERP RS		5.7
gMVP		0.69

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: rs267607003; hg19: chr10-112572068;