11-47343086-G-T

Variant names:

• chr11-47343086-G-T
• rs370412052
• NM_000256.3:c.1286C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_000256.3(MYBPC3):​c.1286C>A​(p.Ala429Glu) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A429V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.65

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 Likely_pathogenic. Variant got 7 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47343086-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.751

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.1286C>A	p.Ala429Glu	missense_variant	Exon 15 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1286C>A	p.Ala429Glu	missense_variant	Exon 15 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.1286C>A	p.Ala429Glu	missense_variant	Exon 14 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.1286C>A		non_coding_transcript_exon_variant	Exon 15 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 31, 2011

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted Ala429Glu (aka A429E) at the protein level and c.1286 C>A at the cDNA level. The Ala429Glu variant in the MYBPC3 gene has not been reported previously as a disease causing mutation nor as a benign polymorphism, to our knowledge. Ala429Glu results in a non conservative amino acid substitution of a non polar Alanine with a negatively charged Glutamic acid at a residue that is conserved across species. In addition, the Ala429Glu variant was not detected in up to 600 alleles from control individuals of Caucasian and African American ancestry, indicating it is not a common benign variant in these populations. However, data from ethnically matched controls is not available, therefore we cannot evaluate if Ala429Glu may be a population specific benign variant. In summary, with the clinical and molecular information available at this time, we cannot equivocally determine whether the Ala429Glu variant is a disease causing mutation or a rare benign variant. The variant is found in HCM panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
CardioboostCm	Benign	0.0088
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.1	L;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.3	D;.;D
REVEL	Benign	0.27
Sift	Benign	0.12	T;.;T
Sift4G	Uncertain	0.0030	D;D;D
Vest4		0.74
MVP		0.82
MPC		0.88
ClinPred		0.96	D
GERP RS		4.7
Varity_R		0.46
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs370412052; hg19: chr11-47364637;