chr10-110821356-G-A

Variant names:

• chr10-110821356-G-A
• rs397516607
• NM_001134363.3:c.2737G>A

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3 PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_001134363.3(RBM20):​c.2737G>A​(p.Glu913Lys) 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 (★★). ClinVar reports functional evidence for this variant: "SCV000060629: RNA sequencing and RT-PCR performed on heart tissue from a patient harboring this variant as well as in vitro studies using transfected cells suggest that this variant affects RBM20 protein function (Beqqali 2016 PMID 27496873, Khan 2016 PMID 27531932, van den Hoogenhof 2018 PMID 29650543)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E913V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 9.36
• Publications: 17 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), G2P, Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000060629: RNA sequencing and RT-PCR performed on heart tissue from a patient harboring this variant as well as in vitro studies using transfected cells suggest that this variant affects RBM20 protein function (Beqqali 2016 PMID 27496873, Khan 2016 PMID 27531932, van den Hoogenhof 2018 PMID 29650543).; SCV004812463: Reduced RBM20 protein expression was also demonstrated in an in vitro cell line assay indicating that this variant impacts protein function (PMID: 27496873).; SCV000236360: Published functional studies demonstrate that E913K results in reduced RBM20 protein expression, which alters titin splicing in the heart (PMID: 27496873, 27531932); SCV000924914: This variant leads to lower RBM20 protein levels by affecting protein stability. This then causes altered splicing of titin (TTN) in the cardiomyocytes, resulting in a shift from the more stiff N2B isoform to the more compliant titin isoform N2BA, an increased sarcomere resting length, and decreased length-dependent activation (impaired Frank-Starling mechanism). PMID:24076290; SCV000768943: Experimental studies have shown that this missense change affects RBM20 function (PMID: 27496873).; SCV002768085: "This variant has strong functional evidence supporting abnormal protein function. Studies with both an affected individual’s heart cells and cell lines have showed that this variant strongly decreases protein levels. In addition, it alters TTN gene splicing and protein isoform composition, leading to an increase in the larger titin isoform." PMID:27496873
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 29 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 chr10-110821357-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2125396.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.768
• PP5: Variant 10-110821356-G-A is Pathogenic according to our data. Variant chr10-110821356-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 43998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134363.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBM20	NM_001134363.3	MANE Select	c.2737G>A	p.Glu913Lys	missense	Exon 11 of 14	NP_001127835.2	Q5T481

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBM20	ENST00000369519.4	TSL:1 MANE Select	c.2737G>A	p.Glu913Lys	missense	Exon 11 of 14	ENSP00000358532.3	Q5T481
	RBM20	ENST00000961386.1		c.2767G>A	p.Glu923Lys	missense	Exon 11 of 14	ENSP00000631445.1
	RBM20	ENST00000718239.1		c.2737G>A	p.Glu913Lys	missense	Exon 11 of 14	ENSP00000520684.1	Q5T481

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Dilated cardiomyopathy 1DD (2)
2	-	-	not provided (2)
2	-	-	Primary dilated cardiomyopathy (2)
1	-	-	Cardiomyopathy (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Left ventricular noncompaction cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	31
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.21	D
PhyloP100		9.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.12	T
Vest4		0.78
MutPred		0.39		Gain of ubiquitination at E913 (P = 0.006)
MVP		0.74
ClinPred		0.98	D
GERP RS		5.8
gMVP		0.55
Mutation Taster		=16/84	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397516607; hg19: chr10-112581114; COSMIC: COSV65706173; COSMIC: COSV65706173;