rs1555121215

Positions:

• chr11-47337486-A-G

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.2507T>C​(p.Met836Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,648 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. M836V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 8.95

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 Fibronectin type-III 1 (size 96) in uniprot entity MYPC3_HUMAN there are 50 pathogenic changes around while only 6 benign (89%) in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.2507T>C	p.Met836Thr	missense_variant	25/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2507T>C	p.Met836Thr	missense_variant	25/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.2507T>C	p.Met836Thr	missense_variant	24/34	5		A2
MYBPC3	ENST00000544791.1	c.*12T>C		3_prime_UTR_variant, NMD_transcript_variant	25/27	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461648 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727120

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 836 of the MYBPC3 protein (p.Met836Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 454315). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 20, 2023	This missense variant replaces methionine with threonine at codon 836 of the MYBPC3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one individual affected with hypertrophic cardiomyopathy (PMID: 33495597). This variant has not been identified 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 01, 2021

Variant summary: MYBPC3 c.2507T>C (p.Met836Thr) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249066 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2507T>C in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2017

The p.M836T variant (also known as c.2507T>C), located in coding exon 25 of the MYBPC3 gene, results from a T to C substitution at nucleotide position 2507. The methionine at codon 836 is replaced by threonine, an amino acid with similar properties. 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	0.96
CardioboostCm	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T;T;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Pathogenic	3.3	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.4	D;.;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D;.;D
Sift4G	Pathogenic	0.0010	D;D;D
Vest4		0.86
MVP		0.92
MPC		0.89
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.94
gMVP		0.86

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: rs1555121215; hg19: chr11-47359037;