chr11-47342930-G-A

Position:

• chr11-47342930-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000256.3(MYBPC3):​c.1357C>T​(p.Pro453Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.51

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 7 ACMG points.

• PM1: In a domain Ig-like C2-type 3 (size 90) in uniprot entity MYPC3_HUMAN there are 33 pathogenic changes around while only 9 benign (79%) in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922
• PP5: Variant 11-47342930-G-A is Pathogenic according to our data. Variant chr11-47342930-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 217475.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.1357C>T	p.Pro453Ser	missense_variant	16/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1357C>T	p.Pro453Ser	missense_variant	16/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.1357C>T	p.Pro453Ser	missense_variant	15/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.1357C>T		non_coding_transcript_exon_variant	16/27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

-

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 06, 2016

The p.P453S variant (also known as c.1357C>T), located in coding exon 16 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 1357. The proline at codon 453 is replaced by serine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6240 samples (12480 alleles) with coverage at this position. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
CardioboostCm	Uncertain	0.22
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D;T;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.8	H;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-7.6	D;.;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0030	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.84
MVP		0.92
MPC		0.76
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.54
gMVP		0.84

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: rs749310275; hg19: chr11-47364481;