rs727503212

Positions:

• chr11-47347668-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.833del​(p.Gly278GlufsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000508 in 1,573,808 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 3.13

Genes affected

MYBPC3 (HGNC:7551): (myosin binding protein C3) MYBPC3 encodes the cardiac isoform of myosin-binding protein C. Myosin-binding protein C is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. MYBPC3 is expressed exclusively in heart muscle and is a key regulator of cardiac contraction. Mutations in this gene are a frequent cause of familial hypertrophic cardiomyopathy. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-47347668-TC-T is Pathogenic according to our data. Variant chr11-47347668-TC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 164140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47347668-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.833del	p.Gly278GlufsTer22	frameshift_variant	8/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.833del	p.Gly278GlufsTer22	frameshift_variant	8/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.833del	p.Gly278GlufsTer22	frameshift_variant	8/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.833del	p.Gly278GlufsTer22	frameshift_variant, NMD_transcript_variant	8/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151924 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000107 AC: 2 AN: 186304 Hom.: 0 AF XY: 0.0000100 AC XY: 1 AN XY: 100050

Gnomad AFR exome AF: 0.0000959

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000126

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000352 AC: 5 AN: 1421884 Hom.: 0 Cov.: 33 AF XY: 0.00000284 AC XY: 2 AN XY: 703588

Gnomad4 AFR exome AF: 0.0000306

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000366

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151924 Hom.: 1 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74212

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	This sequence change creates a premature translational stop signal (p.Gly278Glufs*22) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is present in population databases (rs727503212, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 24793961, 27532257). ClinVar contains an entry for this variant (Variation ID: 164140). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	May 28, 2019	This variant has been identified in 1 HCM proband as part of our research program. The variant also segregated to an affected third-degree family member (3 meiosis). For further information please feel free to contact us. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jun 18, 2018	The c.833del (p.Gly278Glufs*22) variant in the MYBPC3 gene is predicted to introduce a premature translation termination codon. This variant is rare in the general population database, gnomAD (2/181670). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 24793961, 27532257). This variant is reported in ClinVar (ID: 164140). Therefore, the c.833del (p.Gly278Glufs*22) variant in the MYBPC3 gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 31, 2013	The Gly278fs variant in MYBPC3 has not been reported in individuals with cardiom yopathy. Data from large population studies is insufficient to assess the freque ncy of this variant. This frameshift variant is predicted to alter the protein?s amino acid sequence beginning at position 278 and lead to a premature terminati on codon 22 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Truncating variants in MYBPC3 are established as pathogenic for HCM. In summary, this variant meets our criteria to be classifie d as pathogenic (http://pcpgm.partners.org/LMM) based upon the predicted impact of the variant. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Sep 11, 2018	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Mar 03, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 p.Gly278GlufsX22 Upon initial review, we considered this variant very likely disease causing, given that there is strong evidence that frameshift variants in MYBPC3 cause cardiomyopathy. This variant has not been reported in published literature (as of 1/27/2012), however it is very likely to cause disease because the deletion of the Guanine nucleotide at position 833 causes a shift in the reading frame, changing the amino acid sequence and creating a premature stop codon. This would be predicted to either lead to a truncated protein or a no protein production due to nonsense-mediate mRNA decay. Both protein truncating and null variants in MYBPC3 have been associated with cardiomyopathy. This variant is not listed in dbSNP or 1000 genomes (as of 1/27/2012). The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~4,700 Caucasian and African American individuals (as of 1/27/2012). However, a missense variant at that same codon is present in 1/3308 Caucasians and 47/1629 African-Americans. Given these data, we think it is likely that this variant causes cardiomyopathy. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2023	Not observed at a significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24793961, 27532257, 30282064, 31447099, 33673806, 34135346) -

Hypertrophic cardiomyopathy 4 Pathogenic:3

Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Dec 10, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 12, 2023	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Oct 13, 2021	ACMG codes:PVS1; PS4M; PM2; PP5 -

Cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 08, 2023	This variant deletes 1 nucleotide in exon 8 of the MYBPC3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 30282064), in an individual affected with sudden cardiac death due to hypertrophic cardiomyopathy (PMID: 34135346), as well as in an asymptomatic individual aged 70 years and older without a history of cardiovascular events (PMID: 34135346). This variant has been identified in 2/186304 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Aug 06, 2020	- -

Left ventricular noncompaction 10 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 12, 2023

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 29, 2022

The c.833delG pathogenic mutation, located in coding exon 8 of the MYBPC3 gene, results from a deletion of one nucleotide at nucleotide position 833, causing a translational frameshift with a predicted alternate stop codon (p.G278Efs*22). This mutation has been reported in an individual with hypertrophic cardiomyopathy (HCM) and in HCM cohorts (Bos JM et al. Mayo Clin. Proc., 2014 Jun;89:727-37; Walsh R et al. Genet. Med., 2017 02;19:192-203). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

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: rs727503212; hg19: chr11-47369219;