rs375471260

Positions:

• chr11-47351308-C-A
• chr11-47351308-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_000256.3(MYBPC3):​c.223G>T​(p.Asp75Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,425,998 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D75N) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.38

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 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47351308-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.223G>T	p.Asp75Tyr	missense_variant	2/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.223G>T	p.Asp75Tyr	missense_variant	2/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.223G>T	p.Asp75Tyr	missense_variant	2/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.223G>T	p.Asp75Tyr	missense_variant, NMD_transcript_variant	2/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000507 AC: 1 AN: 197134 Hom.: 0 AF XY: 0.00000939 AC XY: 1 AN XY: 106472

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000394

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1425998 Hom.: 0 Cov.: 36 AF XY: 0.00000283 AC XY: 2 AN XY: 705754

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: 0.0000245

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 18, 2023

This missense variant replaces aspartic acid with tyrosine at codon 75 of the MYBPC3 protein. Computational prediction tool indicates that this variant may have a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYBPC3-related disorders in the literature. This variant has been identified in 1/197134 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
CardioboostCm	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D;T;T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.79	D
MutationAssessor	Pathogenic	4.1	H;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.94
MutPred		0.93		Gain of phosphorylation at D75 (P = 0.0424);Gain of phosphorylation at D75 (P = 0.0424);Gain of phosphorylation at D75 (P = 0.0424);
MVP		0.93
MPC		0.92
ClinPred		0.95	D
GERP RS		4.3
Varity_R		0.90
gMVP		0.91

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: rs375471260; hg19: chr11-47372859;