11-47339707-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP4

The NM_000256.3(MYBPC3):c.2011G>A(p.Val671Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. V671F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 7.39

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 1 ACMG points.

PM1

In a domain Ig-like C2-type 5 (size 126) in uniprot entity MYPC3_HUMAN there are 50 pathogenic changes around while only 6 benign (89%) in NM_000256.3

BP4

Computational evidence support a benign effect (MetaRNN=0.42314374).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.2011G>A	p.Val671Ile	missense_variant	21/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.2011G>A	p.Val671Ile	missense_variant	21/35	5	NM_000256.3	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.2011G>A	p.Val671Ile	missense_variant	20/34	5		A2
MYBPC3	ENST00000544791.1 linkuse as main transcript	c.2011G>A	p.Val671Ile	missense_variant, NMD_transcript_variant	21/27	5

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

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:

0.00

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248852

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135052

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461428

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726958

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000105

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jan 09, 2012	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Val671Ile (c.2011G>A) in the MYBPC3 gene. Given that the variant is novel and there is no data connecting it to disease, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant is novel. Sequencing of individuals from the general population has shown that 4-8% of all individuals have a rare or novel variant in one of the HCM genes included in this test (Pan et al 2012). Thus when we find a novel variant in an HCM gene it could either be a causative variant or one of the many benign unique variants we all have. The majority of pathogenic variants in MYBPC3 are nonsense, frameshift, or splicing. Thus when a missense variant is seen very strong evidence is needed to link it to disease. There is no variation at codon 671 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of September 8th, 2015). -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 16, 2015	The p.Val671Ile variant in MYBPC3 has not been previously reported in individual s with cardiomyopathy or in large population studies. Computational prediction t ools and conservation analysis suggest that the p.Val671Ile variant may impact t he protein, though this information is not predictive enough to determine pathog enicity. In summary, the clinical significance of the p.Val671Ile variant is unc ertain. -

Hypertrophic cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 30, 2023	This missense variant replaces valine with isoleucine at codon 671 of the MYBPC3 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 28356264, 30696458). This variant has also been identified in 1/248852 chromosomes 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 01, 2021	This sequence change replaces valine with isoleucine at codon 671 of the MYBPC3 protein (p.Val671Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 28356264). ClinVar contains an entry for this variant (Variation ID: 228865). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Sep 20, 2023

This missense variant replaces valine with isoleucine at codon 671 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: 28356264, 30696458). This variant has been identified in 1/248852 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. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 04, 2019

The p.V671I variant (also known as c.2011G>A), located in coding exon 21 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 2011. The valine at codon 671 is replaced by isoleucine, an amino acid with highly similar properties. This variant was reported in a hypertrophic cardiomyopathy (HCM) cohort, detected in one individual who also had an MYL2 variant; however, clinical details were limited (Gómez J et al. Circ Cardiovasc Genet, 2017 Apr;10:[Epub ahead of print]). This amino acid position is highly 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. -

MYBPC3-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 06, 2023

The MYBPC3 c.2011G>A variant is predicted to result in the amino acid substitution p.Val671Ile. This variant was reported in an individual with dilated cardiomyopathy (Marschall et al. 2019. PubMed ID: 31737537). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-47361258-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

CardioboostCm

Uncertain

0.20

BayesDel_addAF

Benign

-0.024

BayesDel_noAF

Benign

-0.19

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.16

T;T;T

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.42

T;T;T

MetaSVM

Benign

-0.59

MutationAssessor

Benign

1.2

L;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.41

N;.;N

REVEL

Uncertain

0.34

Sift

Benign

0.70

T;.;T

Sift4G

Benign

0.32

T;T;T

Vest4

0.64

MVP

0.83

MPC

0.74

ClinPred

0.94

GERP RS

4.9

Varity_R

0.072

gMVP

0.46

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