11-47333683-G-T

Variant names:

• chr11-47333683-G-T
• NM_000256.3:c.3064C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_000256.3(MYBPC3):​c.3064C>A​(p.Arg1022Ser) 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 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. R1022P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47333682-C-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.3064C>A	p.Arg1022Ser	missense_variant	Exon 29 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3064C>A	p.Arg1022Ser	missense_variant	Exon 29 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.3064C>A	p.Arg1022Ser	missense_variant	Exon 28 of 34	5		ENSP00000382193.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1459074 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 725942

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.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Sep 06, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1022S variant (also known as c.3064C>A), located in coding exon 29 of the MYBPC3 gene, results from a C to A substitution at nucleotide position 3064. The arginine at codon 1022 is replaced by serine, an amino acid with dissimilar properties. This alteration has been detected in Spanish hypertrophic cardiomyopathy (HCM) cohorts with limited clinical detail and possible cohort overlap (Coto E et al. J Mol Diagn. 2012;14:518-24; Gómez J et al. Circ Cardiovasc Genet. 2017;10(2)). In one report, this alteration was detected in an individual with HCM with septal thickness of 25mm and his asymptomatic mother with septal thickness of 18mm (García-Castro M et al. Rev Esp Cardiol. 2009;62:48-56). Other alterations affecting this amino acid (p.R1022P, p.R1022H and p.R1022C) have been reported in the literature in association with HCM with varying levels of clinical detail (Brito D et al. Rev Port Cardiol. 2005;24(9):1137-46; Walsh R et al. Genet Med. 2017;19:192-203; Berge KE et al. Clin Genet. 2014;86(4):355-60). This amino acid position is highly conserved in available vertebrate species. 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 alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
CardioboostCm	Benign	0.042
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;T;T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	0.013	D
MutationAssessor	Benign	2.0	M;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.2	D;.;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D;.;D
Sift4G	Pathogenic	0.0010	D;D;D
Vest4		0.91
MVP		0.91
MPC		0.88
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.74
gMVP		0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-47355234;