rs727504763

Variant names:

• chr10-110821880-CC-G
• rs727504763
• NM_001134363.3:c.3261_3262delCCinsG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001134363.3(RBM20):​c.3261_3262delCCinsG​(p.Ser1087ArgfsTer17) variant causes a frameshift, missense 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, missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4
• Conservation: PhyloP100: 0.0640
• Publications: 2 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), Ambry Genetics, G2P
• 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 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 VariationId is 179284.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.3261_3262delCCinsG	p.Ser1087ArgfsTer17	frameshift_variant, missense_variant	Exon 11 of 14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.3096_3097delCCinsG	p.Ser1032ArgfsTer17	frameshift_variant, missense_variant	Exon 11 of 14		XP_016871592.1
RBM20	XM_017016104.3	c.2877_2878delCCinsG	p.Ser959ArgfsTer17	frameshift_variant, missense_variant	Exon 11 of 14		XP_016871593.1
RBM20	XM_047425116.1	c.2877_2878delCCinsG	p.Ser959ArgfsTer17	frameshift_variant, missense_variant	Exon 11 of 14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.3261_3262delCCinsG	p.Ser1087ArgfsTer17	frameshift_variant, missense_variant	Exon 11 of 14	1	NM_001134363.3	ENSP00000358532.3
RBM20	ENST00000718239.1	c.3261_3262delCCinsG	p.Ser1087ArgfsTer17	frameshift_variant, missense_variant	Exon 11 of 14			ENSP00000520684.1

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:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiovascular phenotype Pathogenic:1 Uncertain:1

Jun 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1;PS4;PP1 -

Jan 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 variant was reported in individual(s) with features consistent with dilated cardiomyopathy (Mazzarotto F et al. Circulation. 2020 Feb;141(5):387-398). 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. Based on the available evidence, the clinical significance of this variant remains unclear. -

Primary dilated cardiomyopathy Pathogenic:1

Mar 23, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 12, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1DD Uncertain:1

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser1087Argfs*17) 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. This variant is present in population databases (no rsID available, gnomAD 0.002%). 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: 2691238). 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. -

not provided Uncertain:1

Aug 30, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.064

Splicing

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

Other links and lift over

dbSNP: rs727504763; hg19: chr10-112581638;