rs730880543

Variant names:

• chr11-47342731-C-T
• rs730880543
• NM_000256.3:c.1471G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1 PP3

The NM_000256.3(MYBPC3):​c.1471G>A​(p.Val491Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000713 in 1,613,870 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V491G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 3.67
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 4

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction 10

  Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000256.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.1471G>A	p.Val491Met	missense_variant	Exon 17 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1471G>A	p.Val491Met	missense_variant	Exon 17 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.1471G>A	p.Val491Met	missense_variant	Exon 16 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.1471G>A		non_coding_transcript_exon_variant	Exon 17 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000562 AC: 14 AN: 249120 AF XY: 0.0000814

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000780 AC: 114 AN: 1461638 Hom.: 0 Cov.: 31 AF XY: 0.0000853 AC XY: 62 AN XY: 727114

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000881 AC: 98 AN: 1111822

Other (OTH) AF: 0.0000331 AC: 2 AN: 60368

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74376

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68044

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.0000622 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000578 AC: 7

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Jan 14, 2022

Phosphorus, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant results in an amino acid substitution of Valine with Methionine at codon 491 of the MYBPC3 gene (transcript: NM_000256.3). This variant has an entry in ClinVar (180940) NM_000256.3(MYBPC3):c.1471G>A (p.Val491Met). This variant occurred in gnomAD with a total MAF of 0 0.0057% and with the highest MAF of 0.0108% in the European population. This position is conserved. In silico functional algorithms predict this variant to be probably damaging (PolyPhen) and deleterious (SIFT). However, no functional studies were performed to confirm either of those predictions. The variant has occurred in the literature in association with hypertrophic cardiomyopathy (HCM) (PMID: 25524337, 20800588). Considering that this is a rare variant and the available evidence is not enough to ascertain its role in disease, it has been classified as Variant of Uncertain Significance. -

Dec 02, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in 1 patient with HCM. It is present in gnomAD at a Max MAF of 0.01% (12 European alleles). It is classified in ClinVar with 1 star as Likely Pathogenic by GeneDx (although their blurb suggests VUS) and VUS by Ambry. The variant is not present in Sarcomere Polyphen. -

Hypertrophic cardiomyopathy Uncertain:2

Oct 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

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 491 of the MYBPC3 protein (p.Val491Met). This variant is present in population databases (rs730880543, gnomAD 0.01%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 20800588, 25351510, 25524337, 33782553; Invitae). ClinVar contains an entry for this variant (Variation ID: 180940). 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. -

Jul 20, 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 491 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 individuals affected with hypertrophic cardiomyopathy (PMID: 20800588, 25351510, 25524337, 27532257, 32841044, 33495596, 33495597, 33782553), and in one individual affected with an unspecified cardiomyopathy (PMID: 37477868). This variant has also been identified in 14/249120 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. -

Cardiomyopathy Uncertain:1

Apr 26, 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 491 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 individuals affected with hypertrophic cardiomyopathy (PMID: 20800588, 25351510, 25524337, 27532257, 32841044, 33495596, 33495597, 33782553), and in one individual affected with an unspecified cardiomyopathy (PMID: 37477868). This variant has also been identified in 14/249120 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;C3715165:Left ventricular noncompaction 10 Uncertain:1

Dec 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Oct 30, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The V491M variant of uncertain significance in the MYBPC3 gene has been reported in association with HCM (Coppini et al., 2014; Lopes et al., 2015; Walsh et al., 2017). This variant has been identified in at least two unrelated individuals referred for HCM genetic testing at GeneDx. The V491M variant is observed in 12/111,626 (0.1%) of alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). V491M is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, other pathogenic or likely pathogenic variants at a nearby residue (R495G, R495W, R495Q) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. -

Cardiovascular phenotype Uncertain:1

Dec 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V491M variant (also known as c.1471G>A), located in coding exon 17 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1471. The valine at codon 491 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Millat G et al. Clin Chim Acta, 2010 Dec;411:1983-91; Coppini R et al. J Am Coll Cardiol, 2014 Dec;64:2589-2600; Lopes LR et al. Heart, 2015 Feb;101:294-301; Walsh R et al. Genet Med, 2017 02;19:192-203; Magrì D et al. J Clin Med, 2020 May;9:[ePub ahead of print]). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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	Benign	0.19
CardioboostCm	Uncertain	0.73
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	-0.078	T
MutationAssessor	Uncertain	2.3	M;.;.
PhyloP100		3.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.1	N;.;N
REVEL	Uncertain	0.61
Sift	Uncertain	0.013	D;.;D
Sift4G	Uncertain	0.013	D;D;D
Vest4		0.84
MVP		0.90
MPC		0.79
ClinPred		0.35	T
GERP RS		4.6
Varity_R		0.21
gMVP		0.56
Mutation Taster		=30/70	disease causing

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

Other links and lift over

dbSNP: rs730880543; hg19: chr11-47364282;