rs397515992

Variant names:

• chr11-47335042-G-A
• rs397515992
• NM_000256.3:c.2905C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-47335042-G-A
• chr11-47335042-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.2905C>T​(p.Gln969*) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.00000217 in 1,381,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.2223
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:19
• Conservation: PhyloP100: 3.76

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 18 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 11-47335042-G-A is Pathogenic according to our data. Variant chr11-47335042-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 42669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47335042-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2905C>T	p.Gln969*	stop_gained, splice_region_variant	Exon 27 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2905C>T	p.Gln969*	stop_gained, splice_region_variant	Exon 27 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.2905C>T	p.Gln969*	stop_gained, splice_region_variant	Exon 26 of 34	5		ENSP00000382193.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1381244 Hom.: 0 Cov.: 31 AF XY: 0.00000295 AC XY: 2 AN XY: 677732

Gnomad4 AFR exome AF: 0.00

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: 0.00000282

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Jun 22, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in several patients referred for HCM genetic testing at GeneDx and found to segregate with disease in a relative of one proband; Reported in one patient with DCM (Hazebroek et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense 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: 25525159, 26914223, 20359594, 22267749, 27373729, 9541104, 27532257, 15519027, 18533079, 21302287, 24111713, 26383716, 29540472, 30282064, 31006259, 29398688, 34137518, 24704860, 9541100, 33673806, 32880476, 32746448, 36203036, 34076677, 35653365) -

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYBPC3: PVS1, PM2 -

Jul 19, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy Pathogenic:6

Nov 20, 2017

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This heterozygous nonsense variant in the MYBPC3 gene was identified in a male patient (53 years old) with familial hypertrophic cardiomyopathy -

Nov 18, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The Gln969X variant has been reported in the literature in at least 2 individual s with clinical features of HCM (Yu 1998, Van Driest 2004) and in our laboratory in three other individuals with HCM. The Gln969X variant leads to a premature s top at codon 969. This alteration is predicted to lead to a truncated or absent protein. Loss of function variants are an established mechanism of disease for t he MYBPC3 gene. It should be noted that this variant was seen in one family alo ng with a second likely pathogenic variant, suggesting that this variant may hav e a milder effect. In summary, the Gln969X variant is highly likely to be patho genic. -

Jun 26, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes one nucleotide in exon 27 of the MYBPC3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 33673806, 34137518, 35653365, 36203036) and in a large family affected with familial hypertrophic cardiomyopathy (PMID: 9541104). This variant has not been identified 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. -

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Genetics and Genomics Program, Sidra Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln969*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 9541104, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42669). For these reasons, this variant has been classified as Pathogenic. -

Hypertrophic cardiomyopathy 4 Pathogenic:3

May 26, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 09, 2020

Clinical Genetics Laboratory, Region Ostergotland

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS4, PM2, PP5 -

Cardiomyopathy Pathogenic:2

Mar 22, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes one nucleotide in exon 27 of the MYBPC3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 33673806, 34137518, 35653365, 36203036) and in a large family affected with familial hypertrophic cardiomyopathy (PMID: 9541104). This variant has not been identified 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. -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Pathogenic:1

Nov 06, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 1 Pathogenic:1

Jul 21, 2015

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The MYBPC3 Gln969* variant has been observed in multiple unrelated HCM cases (Roncarati R, et al., 2011; Van Driest SL, et al., 2004; Yu B, et al., 1998) and absent in >150 controls (Van Driest SL, et al., 2004; Roncarati R, et al., 2011). Furthermore, this variant is absent from both the 1000 genomes project (http://www.1000genomes.org/) and Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). We have identified the MYBPC3 Gln969* variant in an HCM family where two additional variants in MYBPC3 (Arg668His; "uncertain significance") and MYH7 (Arg1079Gln; "uncertain significance") have also been observed in the family (Girolami F, et al., 2010). MYPBC3 Gln969* was identified in our HCM proband who carried the additional MYH7 Arg1079Gln variant. The proband's affected sister carries this MYBPC3 Gln969* as well as both additional MYBPC3 and MYH7 variants variants (Girolami F, et al., 2010). This MYBPC3 variant results in a premature stop codon in place of glutamine (Gln) at position 969 and predicted to result in a truncated protein. Given that loss-of-function variants in MYBPC3 are an established mechanism of disease in HCM, and that MYBPC3 Gln969* has been observed in other cases of familial HCM, we classify this variant as "pathogenic". -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	41
DANN	Uncertain	0.99
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.97
GERP RS		3.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.22
dbscSNV1_RF	Benign	0.57
SpliceAI score (max)		0.040		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: rs397515992; hg19: chr11-47356593; COSMIC: COSV57025396; COSMIC: COSV57025396;