10-110812310-C-T

Variant names:

• chr10-110812310-C-T
• rs267607003
• NM_001134363.3:c.1913C>T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001134363.3(RBM20):​c.1913C>T​(p.Pro638Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,397,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000552923: Experimental studies have shown that this missense change affects RBM20 function (PMID:22466703)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P638Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 7.57
• Publications: 26 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 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000552923: Experimental studies have shown that this missense change affects RBM20 function (PMID: 22466703).; SCV007096613: "This variant has strong functional evidence supporting abnormal protein function. Functional studies of mutant protein in C2C12 cell culture and human cardiac tissue has shown protein mislocalisation to the cytoplasm (PMID: 32840935);"; SCV000236347: Published functional studies demonstrate a damaging effect as a cell-based splice reporter assay showed complete loss of protein function (Guo et al., 2012) and human cardiac tissue cell culture showed an abnormal cytoplasmic localization of the protein (Gaertner et al., 2020); SCV000060611: "In vitro studies suggest that the p.Pro638Leu variant may impact protein function (Guo 2012)."; SCV000737224: In addition, this alteration has been noted as occurring in the RS-rich hot spot region, and studies have suggested this alteration results in cytoplasmic mislocalization and altered protein function (Guo W et al. Nat Med. 2012;18:766-73; Gaertner A et al. Hum Mutat, 2020 11;41:1931-1943).; SCV004109671: "In addition, functional analysis in vitro, suggests that the p.Pro638Leu variant is deleterious (Guo W et al 2012. PubMed ID: 22466703; Gaertner A et al 2020. PubMed ID: 32840935)."
• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 12 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 chr10-110812310-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 372651.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 10-110812310-C-T is Pathogenic according to our data. Variant chr10-110812310-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 268.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.1913C>T	p.Pro638Leu	missense	Exon 9 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.1913C>T	p.Pro638Leu	missense	Exon 9 of 14	ENSP00000358532.3	Q5T481
	RBM20	ENST00000961386.1		c.1943C>T	p.Pro648Leu	missense	Exon 9 of 14	ENSP00000631445.1
	RBM20	ENST00000718239.1		c.1913C>T	p.Pro638Leu	missense	Exon 9 of 14	ENSP00000520684.1	Q5T481

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1397980 Hom.: 0 Cov.: 32 AF XY: 0.00000290 AC XY: 2 AN XY: 689358

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31576

American (AMR) AF: 0.00 AC: 0 AN: 35660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25154

East Asian (EAS) AF: 0.00 AC: 0 AN: 35702

South Asian (SAS) AF: 0.00 AC: 0 AN: 79190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48714

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1078310

Other (OTH) AF: 0.00 AC: 0 AN: 57980

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Dilated cardiomyopathy 1DD (8)
2	-	-	not provided (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Dilated cardiomyopathy 1A (1)
1	-	-	Dilated cardiomyopathy 1S (1)
1	-	-	Primary dilated cardiomyopathy (1)
1	-	-	RBM20-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.86	D
PhyloP100		7.6
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Vest4		0.86
MutPred		0.71		Loss of glycosylation at P638 (P = 0.0459)
MVP		0.88
ClinPred		1.0	D
GERP RS		5.7
gMVP		0.69
Mutation Taster		=18/82	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: rs267607003; hg19: chr10-112572068;