10-110812297-C-T

Position:

• chr10-110812297-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_001134363.3(RBM20):​c.1900C>T​(p.Arg634Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R634Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 1.11

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 15 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 chr10-110812298-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.819
• PP5: Variant 10-110812297-C-T is Pathogenic according to our data. Variant chr10-110812297-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 411653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-110812297-C-T is described in Lovd as [Pathogenic]. Variant chr10-110812297-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.1900C>T	p.Arg634Trp	missense_variant	9/14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.1735C>T	p.Arg579Trp	missense_variant	9/14		XP_016871592.1
RBM20	XM_017016104.3	c.1516C>T	p.Arg506Trp	missense_variant	9/14		XP_016871593.1
RBM20	XM_047425116.1	c.1516C>T	p.Arg506Trp	missense_variant	9/14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.1900C>T	p.Arg634Trp	missense_variant	9/14	1	NM_001134363.3	ENSP00000358532	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1394920 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 687254

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2023	Reported in multiple unrelated individuals with DCM or left ventricular dysfunction (Li et al, 2010; Refaat et al., 2012; Hazebroek et al., 2018; van Waning et al., 2018; van den Hoogenhof et al., 2018; Pantou et al., 2018; Horvat et al., 2019; Das and Seth, 2021; Liatakis et al., 2021); 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: 30847666, 32880476, 33671899, 34021826, 34322310, 30557877, 22004663, 29892087, 20590677, 29540472, 29447731, 29650543, 32674065, 35653365) -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 10, 2022	PP1_strong, PM1, PM2_supporting, PM5, PS4_moderate -

Dilated cardiomyopathy 1DD Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2024

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 634 of the RBM20 protein (p.Arg634Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy (DCM) (PMID: 20590677, 29447731, 29540472, 29895960, 30557877). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 411653). 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) performed at Invitae indicates that this missense variant is not expected to disrupt RBM20 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects RBM20 function (PMID: 29895960). This variant disrupts the p.Arg634 amino acid residue in RBM20. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19712804, 20590677, 22466703, 29029073). 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. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 05, 2024

The p.R634W pathogenic mutation (also known as c.1900C>T), located in coding exon 9 of the RBM20 gene, results from a C to T substitution at nucleotide position 1900. The arginine at codon 634 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration is located in the highly conserved RSRSP stretch that contains the majority of pathogenic RBM20 mutations (Watanabe T et al. Front Mol Biosci, 2018;5:105). This alteration has been detected in multiple individuals with dilated cardiomyopathy (DCM) and has been reported to segregate with disease in several families (Li D et al. Clin Transl Sci, 2010 Jun;3:90-7; Hazebroek MR et al. Circ Heart Fail, 2018 03;11:e004682; Pantou MP et al. Cardiology, 2018 Dec;141:150-155; van den Hoogenhof MMG et al. Circulation, 2018 09;138:1330-1342; Horvat C et al. Genet. Med., 2019 01;21:133-143; Yao JV et al, 2020 Aug;6:499-502). Functional studies suggest that R634W disrupts the phosphorylation of the RSRSP stretch, causes mislocalization, and leads to diminished splicing regulation activity (Murayama R et al. Sci Rep, 2018 06;8:8970). Another alteration at the same codon, p.R634Q (c.1901G>A), has been detected in individuals with DCM (Li D et al. Clin. Trans. Sci. 2010 Jun;3(3):90-7; Brauch KM et al. J. Am. Coll. Cardiol. 2009 Sep;54(10):930-42). 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	0.69
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.58	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Pathogenic	0.90	D
MutationTaster	Benign	0.97	D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.74
MutPred		0.36		Loss of methylation at R636 (P = 0.0222);
MVP		0.66
ClinPred		0.99	D
GERP RS		2.5
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs796734066; hg19: chr10-112572055;