rs1555120949

Variant names:

• chr11-47335991-G-A
• rs1555120949
• NM_000256.3:c.2623C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000256.3(MYBPC3):​c.2623C>T​(p.His875Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. H875R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.46
• Publications: 0 publications found

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]

MYBPC3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 4

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction 10

  Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2623C>T	p.His875Tyr	missense_variant	Exon 26 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2623C>T	p.His875Tyr	missense_variant	Exon 26 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.2623C>T	p.His875Tyr	missense_variant	Exon 25 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.*128C>T		non_coding_transcript_exon_variant	Exon 26 of 27	5		ENSP00000444259.1
MYBPC3	ENST00000544791.1	n.*128C>T		3_prime_UTR_variant	Exon 26 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1381030 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 679658

African (AFR) AF: 0.00 AC: 0 AN: 30476

American (AMR) AF: 0.00 AC: 0 AN: 35464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22410

East Asian (EAS) AF: 0.00 AC: 0 AN: 36398

South Asian (SAS) AF: 0.00 AC: 0 AN: 73674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3908

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1071032

Other (OTH) AF: 0.00 AC: 0 AN: 56832

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

May 16, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.His875Tyr variant in MYBPC3 has not been previously reported in individual s with cardiomyopathy and data from large population studies is insufficient to assess the frequency of this variant. This variant was predicted to be benign us ing a computational tool clinically validated by our laboratory. This tool's ben ign prediction is estimated to be correct 89% of the time (Jordan 2011). In summ ary, the clinical significance of the p.His875Tyr variant is uncertain. -

not provided Uncertain:1

Mar 02, 2019

Blueprint Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
CardioboostCm	Benign	0.041
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.4	M;.;.
PhyloP100		4.5
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.3	N;.;N
REVEL	Benign	0.17
Sift	Benign	1.0	T;.;T
Sift4G	Benign	0.20	T;T;T
Vest4		0.53
MVP		0.81
MPC		0.85
ClinPred		0.79	D
GERP RS		5.3
Varity_R		0.48
gMVP		0.45
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs1555120949; hg19: chr11-47357542;