rs375776406

chr11-47333936-G-A

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). Synonymous variant affecting the same amino acid position (i.e. L994L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:1
• Conservation: PhyloP100: 4.33

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_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32021305).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.2980C>T	p.Leu994Phe	missense_variant	28/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2980C>T	p.Leu994Phe	missense_variant	28/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.2980C>T	p.Leu994Phe	missense_variant	27/34	5		A2

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152250 Hom.: 0 Cov.: 33

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: 13 AN: 193172 Hom.: 0 AF XY: 0.0000868 AC XY: 9 AN XY: 103730

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.: 0 Cov.: 33 AF XY: 0.000354 AC XY: 250 AN XY: 705616

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: 26 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74380

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.: 0

Bravo AF: 0.000132

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.0000916 AC: 11

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	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. -
Uncertain significance, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Mar 11, 2015	- -
Uncertain significance, no assertion criteria provided	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Jun 03, 2019	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". -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	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. -

Cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 02, 2024	This missense variant replaces leucine with phenylalanine at codon 994 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 one 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 a cohort of individuals affected with sudden unexplained death (PMID: 29247119) and in one individual affected with 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 16, 2023	- -

Hypertrophic cardiomyopathy 4 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 26, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 06, 2023

Identified in a father and son with hypertrophic cardiomyopathy; however, these two individuals also harbored a pathogenic variant in the MYH7 gene (Burns et al., 2017); Identified in a cohort of individuals with sudden unexplained deaths, however, no additional clinical information was provided, and it is unclear if this individual had variants identified in other genes (Lin et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24510615, 28790153, 29247119, 22958901) -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 10, 2023

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 26, 2018

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	T
BayesDel_noAF	Benign	-0.32
Cadd	Uncertain	26
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	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	0.72	N;.;.
MutationTaster	Benign	0.90	D;D;D
PrimateAI	Uncertain	0.54	T
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	T
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

Other links and lift over

dbSNP: rs375776406; hg19: chr11-47355487;