10-110812298-G-T

Position:

• chr10-110812298-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3 PP5_Moderate

The NM_001134363.3(RBM20):​c.1901G>T​(p.Arg634Leu) variant causes a missense change involving the alteration of a 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 Likely 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: Likely pathogenic criteria provided, single submitter P:2
• 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 Likely_pathogenic. Variant got 9 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, 0.807
• PP5: Variant 10-110812298-G-T is Pathogenic according to our data. Variant chr10-110812298-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 689585.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.1901G>T	p.Arg634Leu	missense_variant	9/14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.1736G>T	p.Arg579Leu	missense_variant	9/14		XP_016871592.1
RBM20	XM_017016104.3	c.1517G>T	p.Arg506Leu	missense_variant	9/14		XP_016871593.1
RBM20	XM_047425116.1	c.1517G>T	p.Arg506Leu	missense_variant	9/14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.1901G>T	p.Arg634Leu	missense_variant	9/14	1	NM_001134363.3	ENSP00000358532.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1395174 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 687380

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: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Primary dilated cardiomyopathy Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Institute of Human Genetics, University of Wuerzburg

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- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2018

The p.R634L variant (also known as c.1901G>T), located in coding exon 9 of the RBM20 gene, results from a G to T substitution at nucleotide position 1901. The arginine at codon 634 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been detected in two related individuals reported to have left ventricular non-compaction (Sedaghat-Hamedani F et al. Eur. Heart J., 2017 Dec;38:3449-3460). In addition, other alterations at this amino acid (p.R634W and p.R634Q) have been reported in individuals with dilated cardiomyopathy (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):930-41). This amino acid position is highly conserved in available vertebrate species and is located in the conserved RS domain which may be involved in protein-protein interactions that are required for proper function in regulation of mRNA splicing. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Pathogenic	0.87	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Vest4		0.73
MutPred		0.41		Loss of MoRF binding (P = 0.014);
MVP		0.81
ClinPred		0.98	D
GERP RS		5.7
gMVP		0.74

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: rs267607001; hg19: chr10-112572056;