11-47332931-C-T

Variant names:

• chr11-47332931-C-T
• rs121909378
• NM_000256.3:c.3373G>A

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:6
• Conservation: PhyloP100: 0.849

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.3373G>A	p.Val1125Met	missense_variant	Exon 31 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3373G>A	p.Val1125Met	missense_variant	Exon 31 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.3373G>A	p.Val1125Met	missense_variant	Exon 30 of 34	5		ENSP00000382193.2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152166 Hom.: 0 Cov.: 32

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: 6 AN: 242286 Hom.: 0 AF XY: 0.0000152 AC XY: 2 AN XY: 131568

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: 28 AN: 1458392 Hom.: 0 Cov.: 34 AF XY: 0.0000207 AC XY: 15 AN XY: 725114

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: 6 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74332

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.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:1 Uncertain:2

Apr 05, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is present in population databases (rs121909378, gnomAD 0.01%). This missense change has been observed in individuals with MYBPC3-related conditions (PMID: 28356264, 29493010, 33782553; internal data). 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. -

Hypertrophic cardiomyopathy 4 Pathogenic:1 Uncertain:1

Sep 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 09, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Uncertain:1

Aug 07, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with methionine at codon 1125 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. 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 splice 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

Oct 17, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 was reported in individual(s) with features consistent with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) (G&oacute;mez J et al. Circ Cardiovasc Genet, 2017 Apr;10; Walsh R et al. Genet. Med., 2017 02;19:192-203; Mahdieh N et al. J. Clin. Lab. Anal., 2018 Mar; 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; Ambry internal data). 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 borderline hypertrophy (Frank-Hansen R et al. Eur. J. Hum. Genet., 2008 Sep;16:1062-9). 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. Based on the available evidence, the clinical significance of this variant 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	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	23
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	N
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Benign	-0.39	T
MutationAssessor	Pathogenic	3.2	M;.;.
PrimateAI	Uncertain	0.64	T
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	D
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

Other links and lift over

dbSNP: rs121909378; hg19: chr11-47354482;