11-47338631-G-T

Position:

• chr11-47338631-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_000256.3(MYBPC3):​c.2197C>A​(p.Arg733Ser) 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. 14/22 in silico tools predict a benign 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. R733C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.66

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 4 ACMG points.

• PM1: In a strand (size 4) in uniprot entity MYPC3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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 chr11-47338631-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.2396346).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2197C>A	p.Arg733Ser	missense_variant	23/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2197C>A	p.Arg733Ser	missense_variant	23/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.2197C>A	p.Arg733Ser	missense_variant	22/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.2197C>A	p.Arg733Ser	missense_variant, NMD_transcript_variant	23/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 01, 2012

p.Arg733Ser (CGC>AGC):c.2197 C>A in exon 23 of the MYBPC3 gene (NM_000256.3) The Arg733Ser variant in the MYBPC3 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Although Arg733Ser results in a non-conservative amino acid substitution of positively charged Arginine with a neutral, polar Serine, the Arg733 position that not uniformly conserved across species. As a result, in silico analysis predicts Arg733Ser likely has a benign effect on the protein structure/function. However, a different mutation at the same codon (Arg733Ser) has been reported in association with HCM (Van Driest S et al., 2004). In addition, the NHLBI ESP Exome Variant Server reports Arg733Ser was not observed in approximately 4,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations.In summary, the clinical significance of Arg733Ser in the MYBPC3 gene is currently unknown. The variant is found in HCM panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
CardioboostCm	Benign	0.0064
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.11	T;T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.081
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.60	N;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.45	N;.;N
REVEL	Benign	0.098
Sift	Benign	1.0	T;.;T
Sift4G	Benign	0.45	T;T;T
Vest4		0.42
MVP		0.83
MPC		0.73
ClinPred		0.76	D
GERP RS		5.4
Varity_R		0.27
gMVP		0.63

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: rs397515956; hg19: chr11-47360182;