11-47346365-G-T

Variant names:

• chr11-47346365-G-T
• rs193922386
• NM_000256.3:c.932C>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.932C>A​(p.Ser311*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,432,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 1.39

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 11-47346365-G-T is Pathogenic according to our data. Variant chr11-47346365-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 36615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47346365-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.932C>A	p.Ser311*	stop_gained	Exon 12 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.932C>A	p.Ser311*	stop_gained	Exon 12 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.932C>A	p.Ser311*	stop_gained	Exon 11 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.932C>A		non_coding_transcript_exon_variant	Exon 12 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1432076 Hom.: 0 Cov.: 32 AF XY: 0.00000282 AC XY: 2 AN XY: 709184

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: 0.00000183

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Nov 10, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in assocation with HCM and one patient with DCM; one patient with childhood onset HCM harbored another variant in the MYBPC3 gene (Waldmller et al., 2008; Berge et al., 2014; Walsh et al., 2017; van Waning et al., 2018); Not observed in large population cohorts (Lek et al., 2016); 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; Reported in ClinVar as pathogenic (ClinVar Variant ID# 36615; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 29447731, 27532257, 20019025, 18258667, 24111713, 22115648) -

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Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Hypertrophic cardiomyopathy Pathogenic:3

Jan 14, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser311X variant in MYBPC3 has been reported in 4 individuals with HCM (Wal dmuller 2008, Nannenberg 2011, Hoedemaekers 2011- in: Michels 2011, doctoral the sis) and was absent from large population studies. This variant has also been id entified by our laboratory in 1 Caucasian individual with HCM. This nonsense var iant leads to a premature termination codon at position 311, which is predicted to lead to a truncated or absent protein. Heterozygous loss-of-function of the M YBPC3 gene is an established disease mechanism in individuals with HCM. In summa ry, this variant meets our criteria to be classified as pathogenic (http://pcpgm .partners.org/LMM) based on the predicted impact of the variant. -

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 12 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 at least five individuals affected with hypertrophic cardiomyopathy (PMID: 22115648, 24111713, 25611685, 27532257, 32841044, 33495596). This variant has also been reported in two individuals from one family affected with noncompaction cardiomyopathy (PMID: 29447731). 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. -

Jun 03, 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.Ser311*) 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 individual(s) with MYBPC3-related conditions (PMID: 18258667, 22115648, 27532257, 29447731). ClinVar contains an entry for this variant (Variation ID: 36615). For these reasons, this variant has been classified as Pathogenic. -

Hypertrophic cardiomyopathy 4 Pathogenic:2

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Sep 21, 2015

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Primary familial hypertrophic cardiomyopathy Pathogenic:1

Jan 17, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYBPC3 c.932C>A (p.Ser311X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 203230 control chromosomes (gnomAD). c.932C>A has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (Waldmuller 2008, Berge 2013, Nannenberg 2011, Walsh 2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Nov 03, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S311* pathogenic mutation (also known as c.932C>A), located in coding exon 12 of the MYBPC3 gene, results from a C to A substitution at nucleotide position 932. This changes the amino acid from a serine to a stop codon within coding exon 12. This alteration has been reported in association with hypertrophic cardiomyopathy (HCM) (Waldmüller S et al. Clin. Chem., 2008 Apr;54:682-7; Nannenberg EA et al. J. Am. Coll. Cardiol., 2011 Nov;58:2406-14; Walsh R et al. Genet. Med., 2017 02;19:192-203; van Waning JI et al. J. Am. Coll. Cardiol., 2018 Feb;71:711-722). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.36	N
Vest4		0.53
GERP RS		4.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs193922386; hg19: chr11-47367916;