rs397515941

Positions:

• chr11-47339742-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PP3_Moderate

The NM_000256.3(MYBPC3):​c.1976T>C​(p.Ile659Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,613,560 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. I659L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 8.73

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 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000256.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.863

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.1976T>C	p.Ile659Thr	missense_variant	21/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1976T>C	p.Ile659Thr	missense_variant	21/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.1976T>C	p.Ile659Thr	missense_variant	20/34	5		A2
MYBPC3	ENST00000544791.1	c.1976T>C	p.Ile659Thr	missense_variant, NMD_transcript_variant	21/27	5

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152038 Hom.: 0 Cov.: 33

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461522 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727046

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152038 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74260

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: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Mar 10, 2011	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 p.Ile659Thr This variant is novel. This variant results in isoleucine at codon 659 replaced by threonine, an amino acid with a few similar properties. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. Mutation taster predicts this variant to be disease-causing. The isoleucine at codon 659 is conserved across species, as are neighboring amino acids. No other variants have been reported in association with disease at this codon or at nearby codons. In total the variant has not been seen in ~6,500 individuals from publicly available population datasets. There is no variation at codon 659 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 9/20/13). Note that this dataset does not match the patient's ancestry (Mexico/N. American). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 9/20/13). -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 11, 2012	Variant classified as Uncertain Significance - Favor Pathogenic. The Ile659Thr v ariant in MYBPC3 has not been reported in the literature nor been detected in la rge and broad populations (European and African American) screened by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). This low frequency is consistent with a disease causing role but insufficient to establish this wit h confidence. Our laboratory has identified this variant 1 infant with DCM. Comp utational analyses (biochemical amino acid properties, conservation, AlignGVGD, and SIFT) suggest that this variant may impact the protein, though this informat ion is not predictive enough to determine pathogenicity. Additional studies are needed to fully assess its clinical significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 17, 2021	Variant summary: MYBPC3 c.1976T>C (p.Ile659Thr) results in a non-conservative amino acid change in 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 249216 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1976T>C has been reported in the literature as a variant of uncertain clinical significance (VUS) in at-least one individual with a clinical diagnosis of Dilated Cardiomyopathy who underwent a comprehensive genetic assessment on a panel of 19 genes at a reference laboratory (example, Pugh_2014). This individual has been subsequently cited by others (example, Walsh_2017). These report(s) do 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hypertrophic cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 06, 2023	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 659 of the MYBPC3 protein (p.Ile659Thr). This variant is present in population databases (rs397515941, gnomAD 0.007%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 24503780, 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 42590). 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	Oct 23, 2023	This missense variant replaces isoleucine with threonine at codon 659 of the MYBPC3 protein. Computational prediction suggests that this variant may have 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 1 individual affected with dilated cardiomyopathy (PMID: 27532257). This variant has been identified in 1/31386 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 4;C3715165:Left ventricular noncompaction 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 16, 2021

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 09, 2020

Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 42590; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 27532257, 24503780) -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2023

The p.I659T variant (also known as c.1976T>C), located in coding exon 21 of the MYBPC3 gene, results from a T to C substitution at nucleotide position 1976. The isoleucine at codon 659 is replaced by threonine, an amino acid with similar properties. This variant has been detected in an infant with dilated cardiomyopathy; however it was also detected in the unaffected mother, and the proband's father was reported to have left ventricular hypertrophy (Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8). 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	Uncertain	0.44
CardioboostCm	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;T;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	2.0	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.9	D;.;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D;.;D
Sift4G	Pathogenic	0.0010	D;D;D
Vest4		0.91
MVP		0.94
MPC		0.91
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.51
gMVP		0.93

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: rs397515941; hg19: chr11-47361293; COSMIC: COSV57027520;