chr11-47332931-C-T

Position:

chr11-47332931-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_000256.3(MYBPC3):c.3373G>A(p.Val1125Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,610,558 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:6

Conservation

PhyloP100: 0.849

Variant links:

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]

MYBPC3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.3373G>A	p.Val1125Met	missense_variant	31/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.3373G>A	p.Val1125Met	missense_variant	31/35	5	NM_000256.3	ENSP00000442795	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.3373G>A	p.Val1125Met	missense_variant	30/34	5		ENSP00000382193	A2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000576

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:

0.0000248

AC:

AN:

242286

Hom.:

AF XY:

0.0000152

AC XY:

AN XY:

131568

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000297

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000364

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1458392

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

725114

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000226

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.000576

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

Alfa

AF:

0.0000574

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:1Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 29, 2023	This missense change has been observed in individuals with MYBPC3-related conditions (PMID: 28356264, 29493010, 33782553; Invitae). This variant is present in population databases (rs121909378, gnomAD 0.01%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1125 of the MYBPC3 protein (p.Val1125Met). ClinVar contains an entry for this variant (Variation ID: 8604). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 05, 2019	Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in one infant who died of SIDS (Dewar 2017). It was also reported in one Iranian individual with DCM where an in silico study showed that it might be pathogenic (Mahdieh 2018). The variant has also been reported in a patient who was compound het for this variant and the c.960-1G>C variant. Her brother also had both variants and was affected but her mother and son who only had the c.906-1G>C variant were unaffected. Her nephew who had just the V1125M variant was mildly affected (Frank-Hansen 2008). Classified as VUS favour pathogenic in Walsh 2017. Clinvar: VUS (GeneDx, Invitae). Gnomad: 0.01% (1 allele). -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	This missense variant replaces valine with methionine at codon 1125 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 22267749, 27532257, 28356264, 32841044, 33782553). Some of these individuals also carried a different pathogenic variant in the same gene (PMID: 22267749). This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 29493010), in an individual affected with suspected drug-induced long QT syndrome (PMID: 31376648), and in an individual affected with sudden unexplained death (PMID: 28807990). This variant has been identified in 7/273636 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hypertrophic cardiomyopathy 4

Pathogenic:1Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2008	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 09, 2023	- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 28, 2023

This missense variant replaces valine with methionine at codon 1125 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 22267749, 27532257, 28356264, 32841044, 33782553). Some of these individuals also carried a different pathogenic variant in the same gene (PMID: 22267749). This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 29493010), in an individual affected with suspected drug-induced long QT syndrome (PMID: 31376648), and in an individual affected with sudden unexplained death (PMID: 28807990). This variant has been identified in 7/273636 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 17, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21415409, 27532257, 28807990, 29493010, 22267749, 28356264, 31376648, 34426522, 33782553, 35653365, 27585509, 18337725) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2023

The p.V1125M variant (also known as c.3373G>A), located in coding exon 31 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 3373. The valine at codon 1125 is replaced by methionine, an amino acid with highly similar properties. This variant has been detected in sudden unexplained death and hypertrophic cardiomyopathy (HCM) cohorts; however details were limited and some HCM reports may overlap (Dewar LJ et al. Circ Cardiovasc Genet, 2017 Aug;10; Gómez J et al. Circ Cardiovasc Genet, 2017 Apr;10; Walsh R et al. Genet. Med., 2017 02;19:192-203; Mazzarotto F et al. Genet Med. 2019 Feb;21(2):284-292; Helms AS et al. Circ Genom Precis Med. 2020 Oct;13(5):396-405). This variant co-occurred with a second MYBPC3 variant in affected members of a family with HCM, while the p.V1125M variant occurred alone in one individual with a borderline diagnosis of hypertrophy (Frank-Hansen R et al. Eur. J. Hum. Genet., 2008 Sep;16:1062-9). This variant has also been detected in an individual with dilated cardiomyopathy (Mahdieh N et al. J. Clin. Lab. Anal., 2018 Mar). This variant was reported in an individual with Fabry disease and HCM who also had a GLA mutation and a second MYBPC3 variant (Favalli V et al. J. Am. Coll. Cardiol., 2016 09;68:1037-50). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

CardioboostCm

Uncertain

0.18

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;T;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Benign

0.30

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Pathogenic

0.38

MetaRNN

Uncertain

0.55

D;D;D

MetaSVM

Benign

-0.39

MutationAssessor

Pathogenic

3.2

M;.;.

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.28

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.0040

D;D;D

Vest4

0.62

MVP

0.87

MPC

0.78

ClinPred

0.66

GERP RS

5.5

Varity_R

0.33

gMVP

0.50

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over