10-110812297-C-G

Variant names:

• chr10-110812297-C-G
• rs796734066
• NM_001134363.3:c.1900C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_001134363.3(RBM20):​c.1900C>G​(p.Arg634Gly) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R634W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.11
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 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 chr10-110812297-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 411653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.1900C>G	p.Arg634Gly	missense_variant	Exon 9 of 14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.1735C>G	p.Arg579Gly	missense_variant	Exon 9 of 14		XP_016871592.1
RBM20	XM_017016104.3	c.1516C>G	p.Arg506Gly	missense_variant	Exon 9 of 14		XP_016871593.1
RBM20	XM_047425116.1	c.1516C>G	p.Arg506Gly	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	c.1900C>G	p.Arg634Gly	missense_variant	Exon 9 of 14	1	NM_001134363.3	ENSP00000358532.3
RBM20	ENST00000718239.1	c.1900C>G	p.Arg634Gly	missense_variant	Exon 9 of 14			ENSP00000520684.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated cardiomyopathy 1DD Uncertain:1

Nov 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 634 of the RBM20 protein (p.Arg634Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RBM20-related conditions. 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%. 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: 20590677, 29447731, 29540472, 29895960, 30557877). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.62	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Pathogenic	0.95	D
PhyloP100		1.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Vest4		0.73
MutPred		0.43		Loss of MoRF binding (P = 0.016);
MVP		0.61
ClinPred		0.99	D
GERP RS		2.5
gMVP		0.77
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs796734066; hg19: chr10-112572055;