11-47337391-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PP3_Strong

The NM_000256.3(MYBPC3):c.2602G>A(p.Gly868Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000443 in 1,580,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. G868D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 7.57

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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.2602G>A	p.Gly868Ser	missense_variant, splice_region_variant	25/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2602G>A	p.Gly868Ser	missense_variant, splice_region_variant	25/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.2602G>A	p.Gly868Ser	missense_variant, splice_region_variant	24/34	5		A2
MYBPC3	ENST00000544791.1	c.*107G>A		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	25/27	5

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151972 Hom.: 0 Cov.: 32

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000614 AC: 14 AN: 227862 Hom.: 0 AF XY: 0.0000647 AC XY: 8 AN XY: 123568

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000595

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000287

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000388

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000476 AC: 68 AN: 1428416 Hom.: 0 Cov.: 33 AF XY: 0.0000581 AC XY: 41 AN XY: 706116

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000457

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000359

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000311

Gnomad4 OTH exome AF: 0.0000338

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151972 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74232

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000331 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 05, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 29, 2023	This missense variant replaces glycine with serine at codon 868 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). However, this variant causes a G>A nucleotide substitution at the last nucleotide of exon 25 of the MYBPC3 gene, and splice site prediction tools suggest that this variant may impact RNA splicing. An experimental mini-gene splicing assay has shown that this variant may cause partially aberrant splicing (PMID: 28679633); the clinical relevance of this observation is not known. This variant has been reported in an individual affected with dilated cardiomyopathy who also carried a pathogenic truncation variant in the TTN gene that could explain the observed phenotype (PMID: 32826072). This variant has also been reported in an individual affected with Wolff-Parkinson-White syndrome, supraventricular tachycardia, and Ebstein anomaly (PMID: 32233023) and in an individual affected with left ventricular noncompaction (PMID: 30471092). This variant has been identified in 14/227862 chromosomes 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. -

Hypertrophic cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 17, 2023	This missense variant replaces glycine with serine at codon 868 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). However, this variant causes a G>A nucleotide substitution at the last nucleotide of exon 25 of the MYBPC3 gene, and splice site prediction tools suggest that this variant may impact RNA splicing. An experimental mini-gene splicing assay has shown that this variant may cause partially aberrant splicing (PMID: 28679633); the clinical relevance of this observation is not known. This variant has been reported in an individual affected with dilated cardiomyopathy who also carried a pathogenic truncation variant in the TTN gene that could explain the observed phenotype (PMID: 32826072). This variant has also been reported in an individual affected with Wolff-Parkinson-White syndrome, supraventricular tachycardia, and Ebstein anomaly (PMID: 32233023) and in an individual affected with left ventricular noncompaction (PMID: 30471092). This variant has been identified in 14/227862 chromosomes 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 31, 2022	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 868 of the MYBPC3 protein (p.Gly868Ser). This variant also falls at the last nucleotide of exon 25, which is part of the consensus splice site for this exon. This variant is present in population databases (rs775890771, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of left ventricular noncompaction (PMID: 34088380). ClinVar contains an entry for this variant (Variation ID: 518630). 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 tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 20, 2020

Variant summary: MYBPC3 c.2602G>A (p.Gly868Ser) 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. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.1e-05 in 227862 control chromosomes (gnomAD, exomes only). This frequency is not significantly higher than expected for a pathogenic variant in MYBPC3 causing Cardiomyopathy (6.1e-05 vs 0.001), allowing no conclusion about variant significance. c.2602G>A has been reported in the literature in a healthy individual (Kapplinger_2014). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 11, 2022

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2022

The p.G868S variant (also known as c.2602G>A), located in coding exon 25 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 2602.This alteration changes the glycine at codon 868 to serine, an amino acid with similar properties. This alteration was observed in a reportedly healthy control cohort in a study of hypertrophic cardiomyopathy genetic testing, and has also been detected in a left ventricular non-compaction cardiomyopathy cohort and a Wolff-Parkinson-White cohort; however details were limited (Kapplinger JD et al. J Cardiovasc Transl Res, 2014 Apr;7:347-61; Richard P et al. Clin. Genet., 2019 Mar;95:356-367; Coban-Akdemir ZH et al. Am J Med Genet A, 2020 06;182:1387-1399). In a minigene assay, this alteration resulted in some aberrant splicing, as did the reference to a lesser degree; however, the physiologic relevance of these data are unclear (Ito K et al. Proc. Natl. Acad. Sci. U.S.A., 2017 07;114:7689-7694). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. The amino acid position is not well conserved in available vertebrate species, and the missense change is predicted to be tolerated 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	Benign	0.19
CardioboostCm	Benign	0.014
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.39
Cadd	Pathogenic	34
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;T
Eigen	Benign	0.0052
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.46	N;.;N
REVEL	Benign	0.12
Sift	Uncertain	0.0050	D;.;D
Sift4G	Uncertain	0.014	D;D;D
Vest4		0.30
MVP		0.84
MPC		0.42
ClinPred		0.22	T
GERP RS		4.5
Varity_R		0.18
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.18		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: rs775890771; hg19: chr11-47358942;