rs376380567

chr10-110812440-T-Achr10-110812440-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001134363.3(RBM20):c.2043T>A(p.Tyr681Ter) variant causes a stop gained 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 (★★). Synonymous variant affecting the same amino acid position (i.e. Y681Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBM20 NM_001134363.3 stop_gained
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.511

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 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.2043T>A	p.Tyr681Ter	stop_gained	9/14	ENST00000369519.4
RBM20	XM_017016103.3	c.1878T>A	p.Tyr626Ter	stop_gained	9/14
RBM20	XM_017016104.3	c.1659T>A	p.Tyr553Ter	stop_gained	9/14
RBM20	XM_047425116.1	c.1659T>A	p.Tyr553Ter	stop_gained	9/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.2043T>A	p.Tyr681Ter	stop_gained	9/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1DD Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 22, 2023

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. ClinVar contains an entry for this variant (Variation ID: 523896). 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. This sequence change creates a premature translational stop signal (p.Tyr681*) in the RBM20 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in RBM20 cause disease. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 30, 2018

The Y681X variant of uncertain significance in the RBM20 gene has not been reported as a pathogenic or benign to our knowledge. Y681X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Furthermore, the Y681X variant is not observed in large population cohorts (Lek et al., 2016). Although, the spectrum of pathogenic RBM20 variants associated with DCM in humans has not been fully elucidated, studies in rats have shown that complete RBM20 deficiency or RBM20 haploinsufficiency, resulting from either homozygous or heterozygous loss of function pathogenic variants, respectively, interfere with titin gene splicing, alter the expression pattern of different titin isoforms, and result in cardiomyopathy with arrhythmia. Similarly, a missense variant in the human RBM20 gene was shown to alter the expression profile of titin isoforms in heart, suggesting a similar disease mechanism (Guo et al., 2012). Nevertheless, the majority of pathogenic RBM20 variants reported to date are missense changes; only two other loss-of-function variants in the RBM20 gene have been reported in association with DCM (Stenson et al., 2014).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. This result cannot be interpreted for diagnosis or used for family member screening at this time. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.080
Cadd	Pathogenic	27
Dann	Uncertain	0.99
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.32	N
MutationTaster	Benign	1.0	A
Vest4		0.85
GERP RS		-7.0

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: rs376380567; hg19: chr10-112572198;