rs397515938

Positions:

• chr11-47339784-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000256.3(MYBPC3):​c.1934C>T​(p.Pro645Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,148 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). Synonymous variant affecting the same amino acid position (i.e. P645P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 9.37

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 7 ACMG points.

• PM1: In a domain Ig-like C2-type 5 (size 126) in uniprot entity MYPC3_HUMAN there are 34 pathogenic changes around while only 4 benign (89%) in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898
• PP5: Variant 11-47339784-G-A is Pathogenic according to our data. Variant chr11-47339784-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42586.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.1934C>T	p.Pro645Leu	missense_variant	21/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1934C>T	p.Pro645Leu	missense_variant	21/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.1934C>T	p.Pro645Leu	missense_variant	20/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.1934C>T		non_coding_transcript_exon_variant	21/27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461148 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726762

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3

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	Jan 05, 2018	The p.Pro645Leu variant in MYBPC3 has been identified by our laboratory in 2 ind ividuals with HCM, one of whom also carried a likely pathogenic variant in MYBPC 3. It was absent from large population studies. This variant has been reported i n ClinVar (Variation ID: 42586). Computational prediction tools and conservation analysis suggest that the p.Pro645Leu variant may impact the protein, though th is information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Pro645Leu variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jun 14, 2016	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2014

p.Pro645Leu (CCC>CTC): c.1934 C>T in exon 21 of the MYBPC3 gene (NM_000256.3) The P645L variant that is likely pathogenic was identified in the MYBPC3 gene. It has not been published as a mutation or reported as a benign polymorphism to our knowledge. The P645L variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P645L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (R654C, R654H) have been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein.Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. Mutations in the MYBPC3 gene have been reported in 20%-30% of patients with autosomal dominant familial hypertrophic cardiomyopathy, and have been reported less frequently in patients with autosomal dominant familial dilated cardiomyopathy (Cirino A et al., 2011; Hershberger R et al., 2009). The variant is found in HCM panel(s). -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Dec 08, 2015

- -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 06, 2019

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. 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. This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257, Invitae). ClinVar contains an entry for this variant (Variation ID: 42586). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 645 of the MYBPC3 protein (p.Pro645Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
CardioboostCm	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;T;T
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Pathogenic	3.4	M;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-9.0	D;.;D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0010	D;D;D
Vest4		0.83
MVP		0.85
MPC		0.84
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.74
gMVP		0.89

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: rs397515938; hg19: chr11-47361335;