11-47332135-A-G

Position:

• chr11-47332135-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PP3_Strong

The NM_000256.3(MYBPC3):​c.3751T>C​(p.Tyr1251His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,340 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5
• Conservation: PhyloP100: 8.94

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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.3751T>C	p.Tyr1251His	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.3751T>C	p.Tyr1251His	missense_variant	33/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.3751T>C	p.Tyr1251His	missense_variant	32/34	5		ENSP00000382193.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461340 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 726952

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: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 18, 2016	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Tyr1251Hi s variant in MYBPC3 has not been previously reported in individuals with cardiom yopathy or in large population studies. Tyrosine (Tyr) at position 1251 is highl y conserved in mammals and across evolutionarily distant species and the change to Histidine (His) was predicted to be pathogenic using a computational tool cli nically validated by our laboratory. This tool's pathogenic prediction is estima ted to be correct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Tyr1251His variant is uncertain. -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Nov 17, 2011	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Tyr1251His (c.3751 T>C) in MYBPC3 Based on the data reviewed below, we consider it a variant of uncertain significance. The variant is novel. It has not been reported previously in association with disease. This is a semi-conservative amino acid substitution, where a neutral, polar Tyrosine residue is exchanged for a positively charged Histidine residue. The Tyrosine at this position is conserved across species. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging, and Mutation Taster predicts the variant to be disease-causing in all three transcripts. Other variants have been reported in association with disease at nearby codons (p.Pro1245Leu, p.Gly1248Arg, p.Ala1255Thr). Legacy names for this variant include Tyr903 and Tyr1250, none of which have any associated literature. In total the variant has not been seen in 6500 published controls and publicly available population datasets. There is no variation at codon 1251 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of May 16, 2013). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of May 16, 2013). -

Hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 27, 2023

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 1251 of the MYBPC3 protein (p.Tyr1251His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 25351510, 33782553, 36578016). ClinVar contains an entry for this variant (Variation ID: 181020). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change alters MYBPC3 gene expression (PMID: 34097875). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 30, 2017

A variant of uncertain significance has been identified in the MYBPC3 gene. The Y1251H variant has been reported as a rare variant in one individual from an HCM-affected cohort (Lopes et al. 2015); however, additional clinical information, segregation data and functional studies were not provided. Nevertheless, this variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Y1251H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Finally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. -

Hypertrophic cardiomyopathy 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 19, 2020

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3A-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult onset conditions, however recessive inheritance results in a more severe early onset phenotype (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to histidine (exon 33). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools, it is highly conserved with a moderate amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (Immunoglobulin I-set domain; NCBI) (N) 0708 - Comparable variants have conflicting previous evidence for pathogenicity. p.(Tyr1251Cys) reported once in a cohort of 874 HCM patients and as a variant of uncertain significance in ClinVar (ClinVar; PMID: 25351510) (N) 0804 - Variant is absent in the population and has previously been described as variant of uncertain significance in multiple independent cases with consistent phenotype (ClinVar, PMID: 25351510, 28408708, 27532257) (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2020

The p.Y1251H variant (also known as c.3751T>C), located in coding exon 33 of the MYBPC3 gene, results from a T to C substitution at nucleotide position 3751. The tyrosine at codon 1251 is replaced by histidine, an amino acid with similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Ingles J et al. Circ Cardiovasc Genet, 2017 Apr;10; Walsh R et al. Genet Med, 2017 02;19:192-203). 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	0.64
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;T;T
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.6	D;.;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.96
MVP		0.95
MPC		0.95
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.96
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs730880601; hg19: chr11-47353686;