rs528940575

Positions:

• chr11-47332203-C-G
• chr11-47332203-C-T

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.3683G>C​(p.Arg1228Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.63

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 7 (size 93) in uniprot entity MYPC3_HUMAN there are 32 pathogenic changes around while only 0 benign (100%) in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.3683G>C	p.Arg1228Pro	missense_variant	33/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3683G>C	p.Arg1228Pro	missense_variant	33/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.3683G>C	p.Arg1228Pro	missense_variant	32/34	5		ENSP00000382193.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461516 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727046

Gnomad4 AFR exome AF: 0.0000299

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 23, 2015

The p.Arg1228Pro variant in MYBPC3 has not been previously reported in individua ls with cardiomyopathy or in large population studies. Arginine (Arg) at positio n 1228 is conserved in mammals but not in evolutionarily distant species. Additi onal computational prediction tools suggest that this variant may impact the pro tein, though this information is not predictive enough to determine pathogenicit y. In summary, the clinical significance of the p.Arg1228Pro variant is uncertai n. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 29, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32746448) -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Nov 30, 2023

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2021

The p.R1228P variant (also known as c.3683G>C), located in coding exon 33 of the MYBPC3 gene, results from a G to C substitution at nucleotide position 3683. The arginine at codon 1228 is replaced by proline, an amino acid with dissimilar properties. This alteration has been reported in a pediatric cardiomyopathy cohort (Burstein DS et al. Pediatr Res, 2021 05;89:1470-1476). 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	0.97
CardioboostCm	Uncertain	0.16
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;T;T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	0.035	D
MutationAssessor	Benign	1.6	L;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.9	D;.;D
REVEL	Uncertain	0.59
Sift	Benign	0.034	D;.;D
Sift4G	Uncertain	0.025	D;D;D
Vest4		0.97
MVP		0.92
MPC		1.0
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs528940575; hg19: chr11-47353754;