11-47343618-T-G

Position:

• chr11-47343618-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000256.3(MYBPC3):​c.1097A>C​(p.Gln366Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.65

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 3 ACMG points.

• PM1: In a domain Ig-like C2-type 2 (size 90) in uniprot entity MYPC3_HUMAN there are 21 pathogenic changes around while only 3 benign (88%) in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38860518).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.1097A>C	p.Gln366Pro	missense_variant	13/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1097A>C	p.Gln366Pro	missense_variant	13/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.1097A>C	p.Gln366Pro	missense_variant	12/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.1097A>C	p.Gln366Pro	missense_variant, NMD_transcript_variant	13/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 45

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 27, 2023	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. ClinVar contains an entry for this variant (Variation ID: 519044). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 366 of the MYBPC3 protein (p.Gln366Pro). -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 30, 2023	This missense variant replaces glutamine with proline at codon 366 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 at least 1 individual affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant has not been identified 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 provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 05, 2020

Reported in a patient referred for hypertrophic cardiomyopathy genetic testing (Walsh et al., 2017); however, additional clinical information was not provided; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 519044; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257) -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 20, 2020

The p.Q366P variant (also known as c.1097A>C), located in coding exon 13 of the MYBPC3 gene, results from an A to C substitution at nucleotide position 1097. The glutamine at codon 366 is replaced by proline, an amino acid with similar properties. This alteration has been reported in a hypertrophic cardiomyopathy cohort; however, clinical details were limited (Walsh R et al. Genet Med, 2017 02;19:192-203). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
CardioboostCm	Uncertain	0.18
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Benign	0.19	T;T;T
Eigen	Benign	0.029
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.81	L;.;.
MutationTaster	Benign	0.52	D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.26
Sift	Benign	0.29	T;T;T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.34	B;.;.
Vest4		0.48
MutPred		0.55		Gain of glycosylation at Q366 (P = 0.0186);Gain of glycosylation at Q366 (P = 0.0186);Gain of glycosylation at Q366 (P = 0.0186);
MVP		0.76
MPC		0.70
ClinPred		0.63	D
GERP RS		3.8
Varity_R		0.53
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -8

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1451314369; hg19: chr11-47365169;