chr11-47333977-C-T

Variant names:

• chr11-47333977-C-T
• rs727503179
• NM_000256.3:c.2939G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_000256.3(MYBPC3):​c.2939G>A​(p.Arg980His) variant causes a missense change. The variant allele was found at a frequency of 0.000012 in 1,585,428 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. R980C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000091 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 4.74
• Publications: 0 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 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.792

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000256.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	NM_000256.3	MANE Select	c.2939G>A	p.Arg980His	missense	Exon 28 of 35	NP_000247.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	ENST00000545968.6	TSL:5 MANE Select	c.2939G>A	p.Arg980His	missense	Exon 28 of 35	ENSP00000442795.1
	MYBPC3	ENST00000399249.6	TSL:5	c.2939G>A	p.Arg980His	missense	Exon 27 of 34	ENSP00000382193.2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

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: 0.00

GnomAD2 exomes AF: 0.0000198 AC: 4 AN: 202388 AF XY: 0.00000914

Gnomad AFR exome AF: 0.0000885

Gnomad AMR exome AF: 0.000101

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000907 AC: 13 AN: 1433218 Hom.: 0 Cov.: 33 AF XY: 0.00000986 AC XY: 7 AN XY: 710262

African (AFR) AF: 0.0000304 AC: 1 AN: 32880

American (AMR) AF: 0.0000741 AC: 3 AN: 40512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25640

East Asian (EAS) AF: 0.00 AC: 0 AN: 38150

South Asian (SAS) AF: 0.00 AC: 0 AN: 81850

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50928

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00000728 AC: 8 AN: 1098254

Other (OTH) AF: 0.0000169 AC: 1 AN: 59284

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74360

African (AFR) AF: 0.000145 AC: 6 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000198 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000167 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiomyopathy Uncertain:2

Jan 21, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with histidine at codon 980 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 (MID: 27532257). This variant has been identified in 4/202388 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.

Jun 05, 2020

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Uncertain:2

Mar 17, 2022

Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2939G>A variant is not present in publicly available population databases like 1000 Genomes, EVS, ExAC and Indian Exome Database. Heterozygous state of the variant is present in Genome Aggregation Database (gnomAD), at a very low frequency. The variant was previously identified in patients affected with hypertrophic cardiomyopathy (PMID:27532257) and reported to HGMD (ID: CM1616999). The variant was also several times reported to ClinVar as uncertain significance, mainly due to lack of established functional studies (Accession: VCV000164054.4). The variant had also been identified in 3 unaffected individuals from 1963 individuals participating in the Jackson Heart Study (PMID:22958901) and had not been reported in individuals with cardiomyopathy. In-silico pathogenicity prediction programs like SIFT, PolyPhen-2, MutationTaster2, CADD etc. predicted this variant to be likely deleterious, however these predictions were not confirmed by any published functional studies.

Nov 12, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hypertrophic cardiomyopathy Uncertain:2

Dec 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 980 of the MYBPC3 protein (p.Arg980His). This variant is present in population databases (rs727503179, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257, 37652022). ClinVar contains an entry for this variant (Variation ID: 164054). 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.

Apr 27, 2023

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 arginine with histidine at codon 980 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 (MID: 27532257). This variant has been identified in 4/202388 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.

not specified Uncertain:1

Jul 17, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Arg980His variant in MYBPC3 has been identified in 3 unaffected individuals from 1963 individuals participating in the Jackson Heart Study (Bick 2012) and h as not been reported in individuals with cardiomyopathy. Data from large populat ion studies is insufficient to assess the frequency of this variant. Computation al analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhe n2, and SIFT) suggest that this variant may impact the protein, though this info rmation is not predictive enough to determine pathogenicity. In summary, additio nal information is needed to fully assess the clinical significance of this vari ant.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
CardioboostCm	Uncertain	0.16
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		4.7
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.59
MVP		0.91
MPC		0.93
ClinPred		0.93	D
GERP RS		5.0
Varity_R		0.44
gMVP		0.64
Mutation Taster		=42/58	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: rs727503179; hg19: chr11-47355528; COSMIC: COSV108024921; COSMIC: COSV108024921;