rs727503207

chr11-47343502-T-Cchr11-47343502-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000256.3(MYBPC3):c.1213A>G(p.Met405Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M405I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4
• Conservation: PhyloP100: 3.19

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_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain Ig-like C2-type 2 (size 90) in uniprot entity MYPC3_HUMAN there are 25 pathogenic changes around while only 8 benign (76%) in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.1213A>G	p.Met405Val	missense_variant	13/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1213A>G	p.Met405Val	missense_variant	13/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.1213A>G	p.Met405Val	missense_variant	12/34	5		A2
MYBPC3	ENST00000544791.1	c.1213A>G	p.Met405Val	missense_variant, NMD_transcript_variant	13/27	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1245704 Hom.: 0 Cov.: 49 AF XY: 0.00 AC XY: 0 AN XY: 618054

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Aug 08, 2022

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 29, 2014

Variant classified as Uncertain Significance - Favor Pathogenic. The Met405Val v ariant in MYBPC3 has been previously reported in 1 adult with HCM (Crehalet 2012 ) and was identified by our laboratory in 2 individuals with HCM (LMM unpublishe d data). This variant was absent from large population studies. Methionine (Met) at position 405 is not conserved in evolutionarily distant species and the chan ge to valine (Val) is present in several birds and reptiles. However, computatio nal prediction tools and in vitro studies (Crehalet 2012) suggest this variant m ay lead to the creation of a novel splice site, which could result in a truncate d or absent protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the Met405Val variant is uncertain. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Dec 14, 2022

PP3, PM2_supporting, PS3_moderate, PS4_supporting -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 20, 2023

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 405 of the MYBPC3 protein (p.Met405Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25611685, 27532257). ClinVar contains an entry for this variant (Variation ID: 164126). 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 tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2023

The c.1213A>G variant (also known as p.M405V), located in coding exon 13 of the MYBPC3 gene, results from an A to G substitution at nucleotide position 1213. The methionine at codon 405 is replaced by valine, an amino acid with highly similar properties. This variant has been reported in hypertrophic cardiomyopathy (HCM) genetic testing cohorts and individuals reported to have HCM; however, clinical details were limited (Crehalet et al. Cardiogen., 2012; 2:e6; Alfares AA et al. Genet. Med., 2015 Nov;17:880-8; Walsh R et al. Genet. Med., 2017 02;19:192-203). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Limited studies suggest that this variant may have some impact on splicing (Crehalet et al. Cardiogen., 2012; 2:e6; Ito K et al. Proc. Natl. Acad. Sci. U.S.A., 2017 07;114:7689-7694). 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	Benign	0.13
CardioboostCm	Uncertain	0.31
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
Cadd	Pathogenic	26
Dann	Benign	0.92
DEOGEN2	Benign	0.12	T;T;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.066
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.10	N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.26	N;N;N
REVEL	Benign	0.078
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.24	T;T;T
Polyphen		0.0090	B;.;.
Vest4		0.68
MutPred		0.37		Loss of disorder (P = 0.1197);Loss of disorder (P = 0.1197);Loss of disorder (P = 0.1197);
MVP		0.80
MPC		0.23
ClinPred		0.43	T
GERP RS		5.0
Varity_R		0.13
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.99		Position offset: 1
DS_DL_spliceai		0.89		Position offset: -10

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

Publications

LitVar

Other links and lift over

dbSNP: rs727503207; hg19: chr11-47365053;