rs397515992

Positions:

• chr11-47335042-G-A

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.Gln969Ter) 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/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2905C>T	p.Gln969Ter	stop_gained, splice_region_variant	27/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2905C>T	p.Gln969Ter	stop_gained, splice_region_variant	27/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.2905C>T	p.Gln969Ter	stop_gained, splice_region_variant	26/34	5		ENSP00000382193	A2

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

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	MYBPC3: PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 19, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2023	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) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Mar 04, 2019	- -

Hypertrophic cardiomyopathy Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 26, 2023	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. -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 18, 2011	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Nov 20, 2017	This heterozygous nonsense variant in the MYBPC3 gene was identified in a male patient (53 years old) with familial hypertrophic cardiomyopathy -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 15, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 42669). 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. This variant is not present in population databases (gnomAD no frequency). 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). -
Pathogenic, no assertion criteria provided	research	Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics	-	- -
Pathogenic, criteria provided, single submitter	research	Genetics and Genomics Program, Sidra Medicine	-	- -

Hypertrophic cardiomyopathy 4 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Region Ostergotland	Sep 09, 2020	PVS1, PS4, PM2, PP5 -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	May 26, 2016	- -

Cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 04, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 22, 2023	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 06, 2021

- -

Hypertrophic cardiomyopathy 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Jul 21, 2015

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
MutationTaster	Benign	1.0	A;A;A
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;