rs375774648

Positions:

chr11-47347666-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000256.3(MYBPC3):c.836G>C(p.Gly279Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000021 in 1,574,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:12

Conservation

PhyloP100: 0.652

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 Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14660418).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.836G>C	p.Gly279Ala	missense_variant	8/35	ENST00000545968.6	NP_000247.2	Q14896-1A5YM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.836G>C	p.Gly279Ala	missense_variant	8/35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.836G>C	p.Gly279Ala	missense_variant	8/34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 linkuse as main transcript	n.836G>C		non_coding_transcript_exon_variant	8/27	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000735

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000214

AC:

AN:

186786

Hom.:

AF XY:

0.0000399

AC XY:

AN XY:

100330

show subpopulations

Gnomad AFR exome

AF:

0.0000956

Gnomad AMR exome

AF:

0.00

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:

0.0000251

Gnomad OTH exome

AF:

0.000207

GnomAD4 exome

AF:

0.0000183

AC:

AN:

1422130

Hom.:

Cov.:

AF XY:

0.0000227

AC XY:

AN XY:

703710

show subpopulations

Gnomad4 AFR exome

AF:

0.0000917

Gnomad4 AMR exome

AF:

0.0000258

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000156

Gnomad4 OTH exome

AF:

0.0000509

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.000253

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000335

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 29, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 03, 2019	This variant has been seen in one patient with HCM (Richard 2003). It's also been reported in an individual who had this and 2 additional MYBPC3 variants in cis (p.Glu441Lys, p.Gln76Ter) and also a variant in MYH7 (p.Ile1927Phe) (Millat 2010). The variant has also been reported in two affected siblings compound heterozygous for this variant and the MYBPC3 Glu258Lys variant, each from one possibly mildly affected parent (Lopes 2014). The variant is in gnomAD at 0.005% (5 alleles) and classified in ClinVar with 2 stars as VUS by CHEO, Stanford, and CSER. In summary, this variant is of uncertain significance but we would lean towards a more likely benign impact. -

Hypertrophic cardiomyopathy

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 20, 2024	This missense variant replaces glycine with alanine at codon 279 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: 20624503, 31513939, 33495597; Lopes 2020). One of these individuals also carried a pathogenic truncation variant in the same gene (PMID: 20624503). This variant has also been reported in one individual affected with dilated cardiomyopathy (PMID: 30871747), and in one individual affected with sudden cardiac death (PMID: 31376648). Additionally, it has been reported in one individual affected with left ventricular outflow tract obstruction who also carried another pathogenic variant in the same gene (PMID: 25127965). This variant has been identified in 7/218120 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 18, 2023	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 279 of the MYBPC3 protein (p.Gly279Ala). This variant is present in population databases (rs375774648, gnomAD 0.005%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy or dilated cardiomyopathy (PMID: 30731207, 30871747, 31513939). ClinVar contains an entry for this variant (Variation ID: 42798). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 21, 2022	This missense variant replaces glycine with alanine at codon 279 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 an individual affected with dilated cardiomyopathy (PMID: 30871747), at least one individual affected with hypertrophic cardiomyopathy (PMID: 31513939, 33495597; Lopes 2020), and one case of sudden cardiac death (PMID: 31376648). This variant has also been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 20624503) and left ventricular outflow tract obstruction (PMID: 25127965), both of whom carried a known pathogenic variant in the same gene that could explain the observed phenotype. This variant has been identified in 7/218120 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Aug 09, 2021	- -

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Mar 28, 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. MYBPC3 p.Gly279Ala Based on the data reviewed, we classify this variant as a variant of uncertain significance. This variant has been reported in 2 presumably unrelated individuals with HCM. Richard et al (2003) identified p.Gly279Ala in one individual with HCM who had no other variants in the nine sarcomere genes analyzed. Millat et al. (2010) reported one individual with HCM who had three variants on one MYBPC3 allele (p.Glu441Lys, p.Gln76Ter, p.Gly279Ala) and also had an additional variant in MYH7 (p.Ile1927Phe). Unfortunately age of onset and severity were not reported. There is no segregation data available for p.Gly279Ala. p.Gly279Ala is located in a conserved region of the MYBPC3 gene coding for the linker 1-2 region of the protein. However, p.Gly279Ala results in a conservative amino acid substitution and an Alanine is present at codon 279 in rodent. Variants in nearby codons (p.Arg273His, p.Gly278Glu, p.Arg282Trp) have been reported in association with HCM. This variant was not identified in 100 control individuals by Richard et al. This variant was not listed in dbSNP, 1000 genomes, or the NHLBI exome project database. -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2024

The p.G279A variant (also known as c.836G>C), located in coding exon 8 of the MYBPC3 gene, results from a G to C substitution at nucleotide position 836. The glycine at codon 279 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Richard P et al. Circulation, 2003 May;107:2227-32; Millat G et al. Eur J Med Genet, 2010 Jul;53:261-7; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754). Additionally, this variant has also been described in dilated cardiomyopathy (DCM), left ventricular outflow tract obstruction, and drug-induced sudden unexplained death cohorts (Lopes LR et al. Int J Cardiol, 2014 Oct;176:1264-7; Cardoso B et al. Rev Port Cardiol, 2017 Mar;36:155-165; Martinez-Matilla M et al. Forensic Sci Int Genet, 2019 09;42:203-212; Sousa A et al. Rev Port Cardiol, 2019 02;38:129-139). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

CardioboostCm

Benign

0.0060

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.20

T;T;T

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.67

T;T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;.;.

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.66

N;N;N

REVEL

Uncertain

0.30

Sift

Benign

0.42

T;T;T

Sift4G

Benign

0.30

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.67

MVP

0.70

MPC

0.24

ClinPred

0.043

GERP RS

3.5

Varity_R

0.034

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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