rs375776406

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_000256.3(MYBPC3):c.2980C>T(p.Leu994Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000363 in 1,577,622 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00038 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:2

Conservation

PhyloP100: 4.33

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 -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.32021305).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.2980C>T	p.Leu994Phe	missense_variant	Exon 28 of 35	ENST00000545968.6	NP_000247.2	Q14896-1A5YM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6 link	c.2980C>T	p.Leu994Phe	missense_variant	Exon 28 of 35	5	NM_000256.3	ENSP00000442795.1		Q14896-1
MYBPC3	ENST00000399249.6 link	c.2980C>T	p.Leu994Phe	missense_variant	Exon 27 of 34	5		ENSP00000382193.2		A8MXZ9

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000673

AC:

AN:

193172

Hom.:

AF XY:

0.0000868

AC XY:

AN XY:

103730

show subpopulations

Gnomad AFR exome

AF:

0.0000915

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:

0.000144

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000384

AC:

547

AN:

1425372

Hom.:

Cov.:

AF XY:

0.000354

AC XY:

250

AN XY:

705616

show subpopulations

Gnomad4 AFR exome

AF:

0.0000307

Gnomad4 AMR exome

AF:

0.00

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:

0.000490

Gnomad4 OTH exome

AF:

0.000169

GnomAD4 genome

AF:

0.000171

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000131

Hom.:

Bravo

AF:

0.000132

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000916

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Uncertain:4

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 leucine with phenylalanine at codon 994 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 hypertrophic cardiomyopathy (PMID: 28790153); this individual also carried a pathogenic variant in the MYH7 gene that could explain the observed phenotype. This variant has also been reported in the cohort of sudden unexplained deaths (PMID: 29247119) and in a case of pediatric dilated cardiomyopathy (PMID: 34935411). This variant has been identified in 19/224572 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. -

Jan 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 994 of the MYBPC3 protein (p.Leu994Phe). This variant is present in population databases (rs375776406, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and/or suffered sudden unexplained death (PMID: 28790153, 29247119). ClinVar contains an entry for this variant (Variation ID: 180992). 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. -

Mar 11, 2015

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 03, 2019

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

The MYBPC3 Leu994Phe variant has been reported in 2 healthy individuals in the Framingham/Jackson Heart Study (Bick AG, et al., 2012) and is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at an allele frequency of 0.00008. We have identified this variant in 2 probands. The first, a SCD case with no determined cause on post mortem, who harboured a RYR2 (Gly3225Ser) variant (Bagnall RD, et al., 2016). The second, a HCM proband, who also harbours another variant (MYH7 Arg652Gly), both variants segregate with an affected first-degree family member (Burns et al., 2017). Computational tools are in agreement and predict a deleterious effect. In summary, the variant has been identified in 2 healthy individuals and is found to segregate with a rare variant in our family. We therefore classify MYBPC3 Leu994Phe as a variant of "uncertain significance". -

Hypertrophic cardiomyopathy 4

Uncertain:2

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.2980C>T (p.Leu994Phe) Variant in MYBPC3 gene has been reported in heterozygous state individual(s) with hypertrophic cardiomyopathy(Lin, Ying et al.,2017). The amino acid Leu at position 994 is changed to a Phe changing protein sequence and it might alter its composition and physico-chemical properties.The variant is 0.008% alleles in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes This variant has been reported to the ClinVar database as Uncertain significance/ Benign. The amino acid change p.Leu994Phe in MYBPC3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The available evidence is currently insufficient to determine the role of this variant in disease. For these reasons, this variant has been classified as Uncertain Significance. -

Jan 26, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiomyopathy

Uncertain:1Benign:1

May 16, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 31, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10

Uncertain:1

Feb 17, 2023

Clinical Genomics Laboratory, Stanford Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Leu994Phe variant in the MYBPC3 gene has been previously reported in an individual with hypertrophic cardiomyopathy (Burns et al., 2017) and 2 individuals with sudden unexplained death (Bagnall et al., 2016; Lin et al., 2017). This variant has also been reported in 1 control participant from a cardiac genetic testing study and in two participants from the Framingham Heart Study/Jackson Heart Study cohort; however, clinical details were limited (Bick et al., 2012; Kapplinger et al., 2014). This variant has also been identified in 16/98514 (European Non-Finnish) chromosomes (19/224572 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is present in ClinVar (VCV000180992.31). Computational tools predict that this variant is neither deleterious nor benign; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Leu994Phe variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: none] -

not provided

Uncertain:1

May 22, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with HCM and sudden unexplained death in published literature; at least one family also harbored a pathogenic variant in the MYH7 gene (PMID: 37652022, 36252119, 29247119, 28790153); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24510615, 22958901, 29247119, 37652022, 36252119, 28790153, 37937776) -

Cardiovascular phenotype

Uncertain:1

Jul 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L994F variant (also known as c.2980C>T), located in coding exon 28 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2980. The leucine at codon 994 is replaced by phenylalanine, an amino acid with highly similar properties. This variant has been described in hypertrophic cardiomyopathy (HCM) and sudden death cohorts, including some cases with additional cardiac variants also detected (Bagnall RD et al. N Engl J Med, 2016 Jun;374:2441-52; Lin Y et al. Circ Cardiovasc Genet, 2017 Dec;10:; Burns C et al. Circ Cardiovasc Genet, 2017 Aug;10:). This alteration has also been reported in a pediatric dilated cardiomyopathy (DCM) cohort (Khan RS et al. J Am Heart Assoc, 2022 Jan;11:e022854). This variant has also been reported in one control subject from a cardiac genetic testing study and in two participants from the Framingham Heart Study/Jackson Heart Study cohort; however, clinical details were limited (Bick AG et al. Am J Hum Genet, 2012 Sep;91:513-9). This amino acid position is not 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. -

Left ventricular noncompaction 10

Benign:1

Jan 26, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

CardioboostCm

Benign

0.089

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;T;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.32

T;T;T

MetaSVM

Benign

-0.32

MutationAssessor

Benign

0.72

N;.;.

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-2.1

N;.;N

REVEL

Benign

0.21

Sift

Benign

0.048

D;.;D

Sift4G

Uncertain

0.0020

D;D;D

Vest4

0.25

MVP

0.79

MPC

0.79

ClinPred

0.23

GERP RS

5.0

Varity_R

0.45

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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