rs373946195

chr11-47350058-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1 BP4_Strong

The NM_000256.3(MYBPC3):c.461T>C(p.Ile154Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000556 in 1,564,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. I154F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:2
• Conservation: PhyloP100: 6.22

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_benign. Variant got -2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 15 uncertain in NM_000256.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.013160944).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.461T>C	p.Ile154Thr	missense_variant	4/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.461T>C	p.Ile154Thr	missense_variant	4/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.461T>C	p.Ile154Thr	missense_variant	4/34	5		A2
MYBPC3	ENST00000544791.1	c.461T>C	p.Ile154Thr	missense_variant, NMD_transcript_variant	4/27	5

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000627

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: 0.0000588

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.0000742 AC: 13 AN: 175200 Hom.: 0 AF XY: 0.0000855 AC XY: 8 AN XY: 93522

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.000188

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: 0.0000139

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000389 AC: 55 AN: 1412196 Hom.: 0 Cov.: 35 AF XY: 0.0000315 AC XY: 22 AN XY: 697886

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.000160

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000200

Gnomad4 NFE exome AF: 0.0000175

Gnomad4 OTH exome AF: 0.0000854

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152280 Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17 AN XY: 74472

Gnomad4 AFR AF: 0.000626

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: 0.0000588

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000195 Hom.: 0

Bravo AF: 0.000208

ESP6500AA AF: 0.000495 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000102 AC: 12

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2016	The I154T variant of uncertain significance in the MYBPC3 gene has been reported previously in one child diagnosed with HCM who also harbored another variant in the MYBPC3 gene, and reported I154T was absent in at least 360 ethnically-matched control alleles (Morita et al., 2008). Nevertheless, the 1000 Genomes Project reports was observed in 5/1322 alleles (0.4%) from individuals of African ancestry, indicating it may be a rare benign variant in this population. Additionally, another clinical laboratory classifies I154T as a variant of uncertain significance (Landrum et al., 2014). The I154T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals; however, T154 is present in several species. Furthermore, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 22, 2015	Variant classified as Uncertain Significance - Favor Benign. The p.Ile154Thr var iant in MYBPC3 has been identified by our laboratory as heterozygous in 1 Caucas ian infant with DCM and as homozygous in 1 child with HCM (Morita 2008, LMM unpu blished data), who also carries another homozygous variant (p.Asp605del) in this gene. The p.Ile154Thr variant has also been identified in 0.2% (5/2428) of Afri can chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinst itute.org; dbSNP rs373946195). Isoleucine (Ile) at position 154 is not conserved in evolutionarily distant species and multiple fish species carry a threonine a t this position. Additionally, the change to threonine (Thr) was predicted to be benign using a computational tool clinically validated by our laboratory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011 ). In summary, while the clinical significance of the p.Ile154Thr variant is unc ertain, these data suggest that it is more likely to be benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 16, 2020	Variant summary: MYBPC3 c.461T>C (p.Ile154Thr) results in a non-conservative amino acid change located in the Immunoglobulin-like domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.4e-05 in 175200 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MYBPC3 causing Cardiomyopathy (7.4e-05 vs 0.001), allowing no conclusion about variant significance. c.461T>C has been reported in the literature in one individual affected with idiopathic cardiac hypertrophy. 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. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS n=6, likely benign n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Mar 01, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hypertrophic cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 21, 2023	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 154 of the MYBPC3 protein (p.Ile154Thr). This variant is present in population databases (rs373946195, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with MYBPC3-related conditions (PMID: 18403758, 32746448). ClinVar contains an entry for this variant (Variation ID: 42756). 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 tolerated. 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	Dec 13, 2023	This missense variant replaces isoleucine with threonine at codon 154 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 32841044) and in an individual affected with dilated cardiomyopathy (PMID: 32746448). This variant has been reported in compound heterozygous state with p.Asp605del in an individual affected with early-onset familial hypertrophic cardiomyopathy (PMID: 18403758, 18761664); this individual also carried an additional pathogenic variant in the MYBPC3 gene. This variant has also been identified in 20/206608 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. -

Cardiomyopathy Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Nov 28, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 20, 2022	This missense variant replaces isoleucine with threonine at codon 154 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 32841044) and in an individual affected with dilated cardiomyopathy (PMID: 32746448). This variant has been reported in compound heterozygous state with p.Asp605del in an individual affected with early-onset familial hypertrophic cardiomyopathy (PMID: 18403758, 18761664); this individual also carried an additional pathogenic variant in the MYBPC3 gene. This variant has also been identified in 20/206608 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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Primary familial hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 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	0.18
CardioboostCm	Benign	0.017
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	21
Dann	Benign	0.74
DEOGEN2	Benign	0.15	T;T;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.013	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.21	N;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.050	N;N;N
REVEL	Benign	0.26
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.018	B;.;.
Vest4		0.72
MVP		0.74
MPC		0.38
ClinPred		0.038	T
GERP RS		3.3
Varity_R		0.18
gMVP		0.19

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: rs373946195; hg19: chr11-47371609;