rs727504763

Positions:

• chr10-110821879-GCC-GG

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001134363.3(RBM20):​c.3261_3262delinsG​(p.Ser1087ArgfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBM20 NM_001134363.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 0.0640

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 11 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
• PP5: Variant 10-110821880-CC-G is Pathogenic according to our data. Variant chr10-110821880-CC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179284.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.3261_3262delinsG	p.Ser1087ArgfsTer17	frameshift_variant	11/14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.3096_3097delinsG	p.Ser1032ArgfsTer17	frameshift_variant	11/14		XP_016871592.1
RBM20	XM_017016104.3	c.2877_2878delinsG	p.Ser959ArgfsTer17	frameshift_variant	11/14		XP_016871593.1
RBM20	XM_047425116.1	c.2877_2878delinsG	p.Ser959ArgfsTer17	frameshift_variant	11/14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.3261_3262delinsG	p.Ser1087ArgfsTer17	frameshift_variant	11/14	1	NM_001134363.3	ENSP00000358532	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2019	Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; The majority of RBM20 variants reported in HGMD in association with cardiomyopathy are missense variants (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 20590677, 19712804, 22004663) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Feb 23, 2017	- -

Primary dilated cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 23, 2017

The p.Ser1087fs variant in RBM20 has been reported by our laboratory in 2 indivi duals with DCM and segregated with disease in 4 affected relatives from 1 family . This variant was absent from large population studies, though the ability of t hese studies to accurately detect indels may be limited. This variant is predict ed to cause a frameshift, which alters the protein?s amino acid sequence beginni ng at position 1087 and leads to a premature termination codon 17 amino acids do wnstream. This alteration is then predicted to lead to a truncated or absent pro tein. In summary, although additional studies are required to fully establish it s clinical significance, the p.Ser1087fs variant is likely pathogenic. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jan 12, 2023

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2021

The c.3261_3262delCCinsG variant, located in coding exon 11 of the RBM20 gene, results from the deletion of two nucleotides and insertion of one nucleotide causing a translational frameshift with a predicted alternate stop codon (p.S1087Rfs*17). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of RBM20 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs727504763; hg19: chr10-112581638;