rs397516037

chr11-47332189-G-A

Variant summary

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

The NM_000256.3(MYBPC3):c.3697C>T(p.Gln1233Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,506 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q1233Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22
• Conservation: PhyloP100: 7.75

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 11-47332189-G-A is Pathogenic according to our data. Variant chr11-47332189-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47332189-G-A is described in Lovd as [Pathogenic]. Variant chr11-47332189-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.3697C>T	p.Gln1233Ter	stop_gained	33/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3697C>T	p.Gln1233Ter	stop_gained	33/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.3697C>T	p.Gln1233Ter	stop_gained	32/34	5		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249238 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135218

Gnomad AFR exome AF: 0.00

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461506 Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10 AN XY: 727046

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: 0.0000117

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000268 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:22

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 05, 2019	The p.Gln1233X variant has been reported in >10 families with HCM and segregated with disease in >10 affected relatives (Erdmann 2001, Ingles 2005, Zeller 2006, Ehlermann 2008, LMM data). This variant has been reported in ClinVar: P (GeneDx, Invitae, Blueprint, Integrated, Ambry, Johns Hopkins), LP (Geneva).This variant has also been identified in 1/66626 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397516037). This nonsense variant leads to a premature termination codon at position 1233, which is predicted to lead to a truncated or absent protein. Nonsense and other MYBPC3 variants resulting in a heterozygous loss of function are strongly associated with HCM. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genetics Bochum, Ruhr University Bochum	Mar 31, 2022	ACMG criteria used to clasify this variant: PVS1_STR, PS4, PM2_SUP, PP1, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	Aug 06, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Gln1233*) 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 (rs397516037, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 11499719, 18957093, 21985754). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42735). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 16, 2023	This variant is predicted to result in loss of protein function through nonsense-mediated or protein truncation. Loss of function is an established mechanism of disease. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM) or referred for HCM-related genetic testing (PMID: 11499719, 16715312, 18409188, 18957093, 21302287, 22455086, 25611685, 27688314, 22515980). This variant has been reported to co-segregate with HCM in multiple families (PMID: 11499719, 16199542, 16715312, 18957093). It is rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). -

not provided Pathogenic:4

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	GeneDx	Nov 14, 2019	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 (ClinVar Variant ID# 42735; ClinVar); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22515980, 27688314, 12974739, 31513939, 18761664, 21415409, 25163546, 25351510, 17655857, 25525159, 25031304, 18409188, 11499719, 16199542, 18403758, 15519027, 18957093, 21302287, 18505755, 16715312, 21985754, 27662471, 27532257, 28615295, 28408708, 28790153, 24510615, 27600940, 30025578, 29121657, 30550750, 31737537, 30847666, 33673806) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 17, 2021	PP1, PM2, PS4, PVS1 -

Hypertrophic cardiomyopathy 4 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Jul 30, 2015	This mutation in the MYBPC3 gene was identified in a female patient with hypertrophic cardiomyopathy. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Region Ostergotland	Mar 24, 2020	PVS1, PS4, PP5, PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 17, 2018	- -

Cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 19, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 18, 2021	This variant changes 1 nucleotide in exon 33 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 individuals affected with hypertrophic cardiomyopathy (PMID: 11499719, 18957093, 21985754, 24510615, 25031304, 25351510, 27600940, 27532257, 28615295). This variant has been identified in 2/249238 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 09, 2021	The p.Q1233* pathogenic mutation (also known as c.3697C>T), located in coding exon 33 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3697. This changes the amino acid from a glutamine to a stop codon within coding exon 33. This alteration has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy (HCM) and has been reported to segregate with disease in families (Erdmann J et al. J Am Coll Cardiol. 2001;38:322-30; Ingles J et al. J Med Genet. 2005;42:e59; Zeller R et al. J Mol Med. 2006;84:682-91; Ehlermann P et al. BMC Med Genet. 2008;9:95; Fokstuen S et al. Hum Mutat. 2008;29:879-85; Tóth T et al. Int J Cardiol. 2011;153:216-9; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Hathaway J et al. BMC Cardiovasc Disord, 2021 03;21:126). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 06, 2016	Variant summary: The MYBPC3 c.3697C>T (p.Gln1233X) variant results in a premature termination codon, predicted to cause a truncated or absent MYBPC3 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121550 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MYBPC3 variant (0.0010005). This variant has been reported in multiple HCM families and patients, with clear co-segregation of the variant with disease. In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Dilated cardiomyopathy 1I Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

KardioGenetik, Herz- und Diabeteszentrum NRW

Sep 26, 2023

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 06, 2021

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Dec 10, 2020

We observed the genetic variant c.3697C>T (p.Q1233*) in MYBPC3 gene in several probands, diagnosed with various cardiomyopathies. The c.3697C>T variant was previously described as pathogenic (PP5 criteria). IT leads to premature stop-codon at 1233 amino acid position in MYBPC3 gene. Nonsense mutations are a well-known cause of MYBPC3-related cardiomyopathies, therefore, PVS1 criteria is applicable for c.3697C>T variant. The c.3697C>T variant has low frequency in large population studies (PM2 criteria). Several online in silico tools predict the c.3697C>T variant to be deleterious (PP3 criteria). Based on these criteria, we consider the c.3697C>T (p.Q1233*) variant to be pathogenic. -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Nov 04, 2015

- -

Left ventricular hypertrophy Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Aug 28, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Pathogenic	42
Dann	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.88
GERP RS		4.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs397516037; hg19: chr11-47353740;