rs376504548

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The NM_000256.3(MYBPC3):c.2873C>T(p.Thr958Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000168 in 1,592,732 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00024 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:4

Conservation

PhyloP100: 4.48

Variant links:

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]

MYBPC3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a domain Fibronectin type-III 2 (size 95) in uniprot entity MYPC3_HUMAN there are 23 pathogenic changes around while only 7 benign (77%) in NM_000256.3

BP4

Computational evidence support a benign effect (MetaRNN=0.14924946).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.2873C>T	p.Thr958Ile	missense_variant	27/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.2873C>T	p.Thr958Ile	missense_variant	27/35	5	NM_000256.3	ENSP00000442795	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.2873C>T	p.Thr958Ile	missense_variant	26/34	5		ENSP00000382193	A2

Frequencies

GnomAD3 genomes

AF:

0.000236

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000982

AC:

AN:

234236

Hom.:

AF XY:

0.000102

AC XY:

AN XY:

127554

show subpopulations

Gnomad AFR exome

AF:

0.0000683

Gnomad AMR exome

AF:

0.0000936

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:

0.000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000161

AC:

232

AN:

1440494

Hom.:

Cov.:

AF XY:

0.000140

AC XY:

100

AN XY:

714468

show subpopulations

Gnomad4 AFR exome

AF:

0.0000306

Gnomad4 AMR exome

AF:

0.000163

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.000190

Gnomad4 OTH exome

AF:

0.000236

GnomAD4 genome

AF:

0.000236

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000321

Hom.:

Bravo

AF:

0.000159

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000241

AC:

ExAC

AF:

0.0000579

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces threonine with isoleucine at codon 958 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 15823648, 18957093, 24793961, 25078086, 27532257, 33495597). This variant has been observed in one infant affected with hypertrophic cardiomyopathy, whose unaffected parent also carried this variant, as well as in one adult who also carried a pathogenic MYBPC3 variant in cis (ClinVar SCV000059185.5). This variant has been identified in 43/265618 chromosomes in the general population by the Genome Aggregation Database (gnomAD), including one homozygous individual. 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	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Apr 05, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 958 of the MYBPC3 protein (p.Thr958Ile). This variant is present in population databases (rs376504548, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with dilated and/or hypertrophic cardiomyopathy (PMID: 15823648, 18957093, 24793961, 25078086, 27532257, 28416588). ClinVar contains an entry for this variant (Variation ID: 42664). 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. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 20, 2016	Variant classified as Uncertain Significance - Favor Benign. The p.Thr958Ile var iant in MYBPC3 has been reported in 4 individuals with HCM, one of whom carried another pathogenic MYBPC3 variant (Kabaeva 2005, Ehlermann 2008, Adalsteinsdotti r 2014, Bos 2014). In addition, this variant has been identified by our laborato ry in 3 individuals with HCM, (including one infant whose unaffected parent also carried this variant, as well as one adult who also carried a pathogenic MYBPC3 variant (in cis)) and 1 individual with DCM. This variant has been identified i n 7/61564 European chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org/; dbSNP rs376504548). Threonine at position 958 is not conserved in evolution and 1 mammal (Bactrian camel) and multiple bird species h ave an isoleucine (Ile) at this position, suggesting that this change may be tol erated. In addition, this change was predicted to be benign using a computationa l 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 cli nical significance of the p.Thr958Ile variant is uncertain, collectively these d ata suggest that it is more likely to be benign. -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 09, 2013	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. p.Thr958Ile (c.2873 C>T) in MYBPC3 Based on the data reviewed below we consider this a variant of uncertain significance. This variant has been seen in 2 presumably unrelated cases of HCM and a case of infantile DCM. It has also been observed in general population and control samples. No segregation is available. Kabaeva et al (2005) reported this variant in a German male diagnosed with HCM at age 25. Ehlermann et al (2008) reported another German case of HCM with this variant. That patient was a male diagnosed at 46 years of age. These two cases appear to be different cases, given the reported ages of diagnosis. GeneDx reports that p.Thr958Ile was identified in an additional unrelated individual who was diagnosed with DCM in infancy and tested in their lab. I could not find any functional or experimental data on this variant or other variants at this or nearby codons reported in association with disease. In silico analysis with polyphen2 predicts this variant to be benign. The threonine at codon 958 is not conserved across species; it is an isoleucine in chickens, and glutamate in c. elegans. The variant has been seen in 3 of 5154 general population samples. Neither Ehlermann et al (2008) or Kabaeva et al (2005) reported control data. There is no variation listed at this codon in dbSNP or 1000 genomes (as of January 27, 2012). However, the variant was observed in 2 of 3346 Caucasian individuals and 0 of 1608 African Americans in the NHLBI Exome Sequencing Project dataset (as of January 27, 2012). The phenotype of those two individuals is not available, however given the way the samples were accrued, we consider this a general population sample unselected for Mendelian cardiac disease. -

Cardiomyopathy

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 07, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 21, 2023	This missense variant replaces threonine with isoleucine at codon 958 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 15823648, 18957093, 24793961, 25078086, 27532257, 33495597). This variant has been observed in one infant affected with hypertrophic cardiomyopathy, whose unaffected parent also carried this variant, as well as in one adult who also carried a pathogenic MYBPC3 variant in cis (ClinVar SCV000059185.5). This variant has been identified in 43/265618 chromosomes in the general population by the Genome Aggregation Database (gnomAD), including one homozygous individual. 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. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	MYBPC3: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2019	This variant is associated with the following publications: (PMID: 25078086, 21415409, 15823648, 18957093, 29247119, 23861362, 23299917, 25637381, 22958901, 27532257, 24793961, 28416588, 28518168) -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 09, 2022

The c.2873C>T (p.T958I) alteration is located in exon 27 (coding exon 27) of the MYBPC3 gene. This alteration results from a C to T substitution at nucleotide position 2873, causing the threonine (T) at amino acid position 958 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

MYBPC3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 13, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

CardioboostCm

Benign

0.0028

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Benign

0.11

T;T;T

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.63

T;T;T

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;.;.

MutationTaster

Benign

0.61

N;N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.34

N;N;N

REVEL

Benign

0.19

Sift

Benign

0.41

T;T;T

Sift4G

Benign

0.11

T;T;T

Vest4

0.15

MVP

0.81

MPC

0.24

ClinPred

0.10

GERP RS

5.2

Varity_R

0.18

gMVP

0.39

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over