rs727503218

Positions:

• chr11-47349896-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PP3_Strong

The NM_000256.3(MYBPC3):​c.532G>A​(p.Val178Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000117 in 1,456,766 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 4.99

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain Ig-like C2-type 1 (size 103) in uniprot entity MYPC3_HUMAN there are 30 pathogenic changes around while only 10 benign (75%) in NM_000256.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.532G>A	p.Val178Met	missense_variant	5/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.532G>A	p.Val178Met	missense_variant	5/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.532G>A	p.Val178Met	missense_variant	5/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.532G>A	p.Val178Met	missense_variant, NMD_transcript_variant	5/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1456766 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 724210

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000227

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000759

Gnomad4 SAS exome AF: 0.0000235

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000901

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 25, 2023	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 178 of the MYBPC3 protein (p.Val178Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (HCM) as well as in individual(s) with left ventricular noncompaction cardiomyopathy and left ventricular noncompaction cardiomyopathy. However, in at least one individual pathogenic allele[s] were also identified in MYBPC3 and/or HCN4, which suggests that this c.532G>A variant may not be the primary cause of disease. (PMID: 20031602, 24111713, 27532257, 29121657, 30165862, 30471092, 34088380; Invitae). ClinVar contains an entry for this variant (Variation ID: 164149). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 13, 2024	This missense variant replaces valine with methionine at codon 178 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 20031602, 24111713, 33495597, 36293497, 36788754). It has also been reported in an individual affected with an unspecified cardiomyopathy (PMID: 30165862) and in an individual affected with left ventricular noncompaction (PMID: 30471092). This variant has not been identified 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 specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 29, 2017

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Val178Met variant in MYBPC3 has been reported in at least 3 individuals with HCM (Ho 2009 ; LMM data), one of which carried this variant in the homozygous state. This va riant also segregated with disease in 1 affected relative. This variant has been identified in 1/105830 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/). This variant has been reported in C linVar (Variant ID: 174794). Computational prediction tools and conservation ana lysis suggest that the p.Val178Met variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, whi le there is some suspicion for a pathogenic role, the clinical significance of t he p.Val178Met variant is uncertain. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jan 21, 2022

This missense variant replaces valine with methionine at codon 178 of the MYBPC3 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein function. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in three individuals affected with hypertrophic cardiomyopathy (PMID: 20031602, 24111713, 33495597), in an individual affected with hypertrophic or restrictive cardiomyopathy (PMID: 30165862), and in an individual affected with left ventricular non-compaction (PMID: 30471092). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2023

The p.V178M variant (also known as c.532G>A), located in coding exon 5 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 532. The valine at codon 178 is replaced by methionine, an amino acid with highly similar properties. This variant has been reported in hypertrophic cardiomyopathy (HCM), left ventricular non-compaction (LVNC), and general cardiomyopathy cohorts; however, limited clinical information was provided and additional cardiac variants were detected in some cases (Ho CY et al. Circ Cardiovasc Genet, 2009 Aug;2:314-21; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Walsh R et al. Genet. Med., 2017 02;19:192-203; Mademont-Soler I et al. PLoS One, 2017 Aug;12:e0181465; Viswanathan SK et al. PLoS ONE, 2017 Dec;12:e0187948; Lu C et al. J Transl Med, 2018 08;16:241; Richard P et al. Clin. Genet., 2019 Mar;95:356-367). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	Uncertain	0.53
CardioboostCm	Uncertain	0.30
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;T;T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.5	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.71
MutPred		0.94		Gain of MoRF binding (P = 0.1068);Gain of MoRF binding (P = 0.1068);Gain of MoRF binding (P = 0.1068);
MVP		0.86
MPC		0.83
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.63
gMVP		0.74

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: rs727503218; hg19: chr11-47371447;