rs397516068

Positions:

• chr11-47348541-C-A
• chr11-47348541-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3 PP5

The NM_000256.3(MYBPC3):​c.655G>T​(p.Val219Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V219L) has been classified as Pathogenic.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 29)
• Consequence: MYBPC3 NM_000256.3 missense, splice_region
• Scores: Splicing: ADA: 0.9972
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 2.08

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 8 ACMG points.

• PM1: In a strand (size 7) in uniprot entity MYPC3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47348541-C-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825
• PP5: Variant 11-47348541-C-A is Pathogenic according to our data. Variant chr11-47348541-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188531.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=2}. Variant chr11-47348541-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.655G>T	p.Val219Phe	missense_variant, splice_region_variant	6/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.655G>T	p.Val219Phe	missense_variant, splice_region_variant	6/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.655G>T	p.Val219Phe	missense_variant, splice_region_variant	6/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.655G>T		splice_region_variant, non_coding_transcript_exon_variant	6/27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152112 Hom.: 0 Cov.: 29

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00000411 AC: 1 AN: 243260 Hom.: 0 AF XY: 0.00000757 AC XY: 1 AN XY: 132108

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000169

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152230 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 74452

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 07, 2023	This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 219 of the MYBPC3 protein (p.Val219Phe). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 20624503, 26914223). ClinVar contains an entry for this variant (Variation ID: 188531). 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 mRNA splicing and is expected to lead to the loss of protein expression (Crehalet et al. 2012. Cardiogenetics; http://dx.doi.org/10.4081/cardiogenetics.2012.e6). This variant disrupts the c.655G nucleotide in the MYBPC3 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 15519027, 20031602, 20031618, 20624503, 26914223). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 19, 2013	The Val219Phe variant in MYBPC3 has been reported in two adults with HCM (Millat 2010, Crehalet 2012) and was absent in large population studies. This variant is located in the first base of the exon, which is part of the 3’ splice region. In vitro studies showed that this variant results in skipping of exon 6 (Crehalet 2012), which is predicted to cause a frameshift and a premature termination codon, leading to a truncated or absent protein. Heterozygous loss-of-function of the MYBPC3 gene is an established disease mechanism in HCM. In summary, this variant is likely to be pathogenic, though additional studies are required to fully establish its clinical significance. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 01, 2022

In vitro studies have shown that c.655 G>T results in the skipping of exon 6, which is expected to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation (Crehalet et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 7446532, 28265379, 27535533, 28679633, 26914223, 20624503, 31589614, 34097875, Crehalet_2012_Cardiogenetics) -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 16, 2017

The c.655G>T variant (also known as p.V219F) is located in coding exon 6 of the MYBPC3 gene. The valine at codon 219 is replaced by phenylalanine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 6. This variant has been reported in several hypertrophic cardiomyopathy (HCM) cohorts (Millat G et al. Eur J Med Genet. 2010;53:261-7; Crehalet H et al. Cardiogenetics. 2012;2:e6; Murphy SL et al. J Cardiovasc Transl Res. 2016;9:153-61). In addition, this alteration causes complete skipping of exon 6 in an in vitro minigene assay (Crehalet H et al. Cardiogenetics. 2012;2:e6). Skipping of exon 6 is expected to lead to a frameshift with a predicted alternative stop (p.V219Rfs*42). A disease-causing mutation in the same nucleotide, c.655G>C, is also reported to lead to skipping of exon 6 (Van Driest SL et al. J. Am. Coll. Cardiol. 2004;44:1903-10; Crehalet H et al. Cardiogenetics. 2012;2:e6; Walsh R et al. Genet. Med. 2017;19:192-203). This nucleotide position is well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice acceptor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
CardioboostCm	Uncertain	0.73
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D;T;T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.2	M;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.76
MutPred		0.57		Gain of ubiquitination at K218 (P = 0.1278);Gain of ubiquitination at K218 (P = 0.1278);Gain of ubiquitination at K218 (P = 0.1278);
MVP		0.93
MPC		0.94
ClinPred		0.95	D
GERP RS		2.9
Varity_R		0.67
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.86
SpliceAI score (max)		0.010		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: rs397516068; hg19: chr11-47370092;