10-110812310-C-G

Position:

• chr10-110812310-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_001134363.3(RBM20):​c.1913C>G​(p.Pro638Arg) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P638L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• 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 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 chr10-110812310-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872
• PP5: Variant 10-110812310-C-G is Pathogenic according to our data. Variant chr10-110812310-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 202063.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.1913C>G	p.Pro638Arg	missense_variant	9/14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.1748C>G	p.Pro583Arg	missense_variant	9/14		XP_016871592.1
RBM20	XM_017016104.3	c.1529C>G	p.Pro510Arg	missense_variant	9/14		XP_016871593.1
RBM20	XM_047425116.1	c.1529C>G	p.Pro510Arg	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>G	p.Pro638Arg	missense_variant	9/14	1	NM_001134363.3	ENSP00000358532.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dilated cardiomyopathy 1DD Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 23, 2022

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Pro6389 amino acid residue in RBM20. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19712804, 22466703). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 202063). This variant has not been reported in the literature in individuals affected with RBM20-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 638 of the RBM20 protein (p.Pro638Arg). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 08, 2017

Although the P638R pathogenic variant in the RBM20 gene has not been published as pathogenic or been reported as benign to our knowledge, it has been identified in two unrelated individuals referred for DCM testing at GeneDx and segregates with DCM in several affected family members of one of these probands. Additionally, a pathogenic variant affecting this same residue (P638L) has been reported to segregate with DCM in multiple individuals from two unrelated families (Brauch et al., 2009). Furthermore, missense variants in nearby residues (R634W, R634Q, R636C, R636S, R636H) in the highly conserved Arginine/Serine-rich (RS) domain have been reported in the Human Gene Mutation Database in association with DCM (Stenson et al., 2014), supporting the functional importance of this residue and this region of the protein. The P638R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and this substitution occurs at a position that is conserved across species. Moreover, in silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, the P638R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 03, 2023

The p.P638R variant (also known as c.1913C>G), located in coding exon 9 of the RBM20 gene, results from a C to G substitution at nucleotide position 1913. The proline at codon 638 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in a cohort of individuals with cardiovascular disease (VanDyke RE et al. J Genet Couns, 2021 Apr;30:503-512). Based on internal structural analysis, this alteration disrupts a characterized motif which has other known pathogenic variants (Watanabe T et al. Front Mol Biosci, 2018 Nov;5:105; Schneider JW et al. Nat Med, 2020 Nov;26:1788-1800; Nishiyama T et al. Sci Transl Med, 2022 Nov;14:eade1633). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	0.84	D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Vest4		0.76
MutPred		0.39		Gain of MoRF binding (P = 0.0092);
MVP		0.86
ClinPred		1.0	D
GERP RS		5.7
gMVP		0.72

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: rs267607003; hg19: chr10-112572068;