rs730880565

Positions:

• chr11-47337722-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1 PP3

The NM_000256.3(MYBPC3):​c.2381C>T​(p.Pro794Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000804 in 1,566,584 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.000053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000083 (1 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 B:5
• Conservation: PhyloP100: 6.54

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a domain Fibronectin type-III 1 (size 96) in uniprot entity MYPC3_HUMAN there are 31 pathogenic changes around while only 3 benign (91%) in NM_000256.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.773

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2381C>T	p.Pro794Leu	missense_variant	24/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2381C>T	p.Pro794Leu	missense_variant	24/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.2381C>T	p.Pro794Leu	missense_variant	23/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.2381C>T		non_coding_transcript_exon_variant	24/27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152076 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000144 AC: 25 AN: 173856 Hom.: 0 AF XY: 0.000172 AC XY: 16 AN XY: 92890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000382

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000789

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000834 AC: 118 AN: 1414508 Hom.: 1 Cov.: 33 AF XY: 0.000107 AC XY: 75 AN XY: 699368

Gnomad4 AFR exome AF: 0.0000310

Gnomad4 AMR exome AF: 0.0000535

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000990

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000221

Gnomad4 OTH exome AF: 0.000153

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152076 Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4 AN XY: 74288

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000820 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000938 AC: 11

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Nov 01, 2017	p.Pro794Leu (c.2381C>T) in exon 24 of the MYBPC3 gene (NM_000256.3; chr11-47359273-G-A) SCICD Classification: variant of uncertain significance, likely benign based on relatively high frequency in the general population, lack of case data and lack of segregation data. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: MYBPC3: Pathogenic variants in MYBPC3 are one of the most common causes of hypertrophic cardiomyopathy (HCM). Splicing and other protein-truncating variants in MYBPC3 are a frequent cause of HCM (Erdmann et al. 2001 & 2003; Stenson et al 2003; Harvard Sarcomere Protein Gene Mutation Database). However, there are several missense variants in MYBPC3 known to cause disease. MYBPC3 encodes cardiac myosin-binding protein C. It binds myosin heavy chain and titin. Phosphorylation of MYBPC3 modulates contraction of the sarcomere. Region level data: Amr et al 2016: patients with HCM with variants in this region are overrepresented compared to controls. Case data (not including our patient): at least 3 · ClinVar: § GeneDx (likely path), Laboratory for Molecular Medicine (VUS) and Blueprint Genetics (VUS): § LMM saw this variant in a whole exome/genome case but was not fully reviewed. § GeneDx saw this variant in one patient with HCM who had another pathogenic variant. However, neither of these variants have been reviewed since updated variant classification guidelines were published § Blueprint has downgraded their classification of this variant to VUS from likely path. · Cases in the literature: none reported Segregation data: none reported Functional data: none reported In silico data (missense variants only): Per the test report, "Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain." Conservation data: The proline at codon 794 is not completely conserved across species. Nearby pathogenic variants at this codon or neighboring codons: A truncating variant at this codon, p.Pro794fs*26, is reported in 1 of ~400 patients with HCM (Van Driest et al 2004). Other truncating variants are nearby (p.Gln791Ter, p.Trp792Valfs, p.Trp792Ter, p.Pro795Leufs, p.Gly799Trpfs). A missense variant at a nearby codon is classified as pathogenic by multiple labs: p.Trp792Arg. Population data: Highest MAF in the South Asian population: 0.079%. The variant was reported online in 27 of 99,709 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 19 of 12,073 individuals of South Asian descent (MAF=0.079%), 1 of 2,571 individuals of "other" descent, 6 of 41,715 individuals of European descent and 1 of 13,128 individuals of Latino descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 23, 2021	Reported as a variant of uncertain significance in association with cardiomyopathy (Whiffin et al., 2017; Kolokotronis et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID# 180968; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31980526, 26582918, 28518168, 32659924) -

Cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 20, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 04, 2023	- -

Hypertrophic cardiomyopathy 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Apr 04, 2024

- -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Blueprint Genetics

Mar 26, 2015

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 09, 2019

The p.Pro794Leu variant in MYBPC3 is classified as likely benign because it has been identified in 0.08% (19/24078) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BS1. -

Hypertrophic cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
CardioboostCm	Benign	0.024
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.41	T;T;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Uncertain	0.0042	D
MutationAssessor	Pathogenic	3.4	M;.;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-7.8	D;D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Vest4		0.78
MVP		0.92
MPC		0.83
ClinPred		0.95	D
GERP RS		4.3
Varity_R		0.51
gMVP		0.78

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: rs730880565; hg19: chr11-47359273;