chr11-47338649-C-A

Variant names:

• chr11-47338649-C-A
• rs564378953
• NM_000256.3:c.2179G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_000256.3(MYBPC3):​c.2179G>T​(p.Val727Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,382 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.85

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a domain Ig-like C2-type 5 (size 126) in uniprot entity MYPC3_HUMAN there are 34 pathogenic changes around while only 4 benign (89%) in NM_000256.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2179G>T	p.Val727Leu	missense_variant	Exon 23 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2179G>T	p.Val727Leu	missense_variant	Exon 23 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.2179G>T	p.Val727Leu	missense_variant	Exon 22 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.2179G>T		non_coding_transcript_exon_variant	Exon 23 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000807 AC: 2 AN: 247856 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134594

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461382 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726972

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:1

Feb 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 727 of the MYBPC3 protein (p.Val727Leu). This variant is present in population databases (no rsID available, gnomAD 0.005%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 33782553). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
CardioboostCm	Benign	0.055
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;T;T
Eigen	Benign	0.045
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.68	D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.5	L;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.8	N;.;N
REVEL	Benign	0.23
Sift	Benign	0.17	T;.;T
Sift4G	Benign	0.097	T;T;T
Vest4		0.73
MVP		0.86
MPC		0.65
ClinPred		0.86	D
GERP RS		5.4
Varity_R		0.21
gMVP		0.67

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

Other links and lift over

dbSNP: rs564378953; hg19: chr11-47360200;