NM_000256.3:c.3407_3409delACT

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM4_SupportingPP5

The NM_000256.3(MYBPC3):​c.3407_3409delACT​(p.Tyr1136del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000435 in 1,608,628 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:16U:2

Conservation

PhyloP100: 8.93
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM4
Nonframeshift variant in NON repetitive region in NM_000256.3. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 11-47332894-AAGT-A is Pathogenic according to our data. Variant chr11-47332894-AAGT-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181102.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=2, Likely_pathogenic=11}. Variant chr11-47332894-AAGT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYBPC3NM_000256.3 linkc.3407_3409delACT p.Tyr1136del disruptive_inframe_deletion Exon 31 of 35 ENST00000545968.6 NP_000247.2 Q14896-1A5YM48

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYBPC3ENST00000545968.6 linkc.3407_3409delACT p.Tyr1136del disruptive_inframe_deletion Exon 31 of 35 5 NM_000256.3 ENSP00000442795.1 Q14896-1
MYBPC3ENST00000399249.6 linkc.3407_3409delACT p.Tyr1136del disruptive_inframe_deletion Exon 30 of 34 5 ENSP00000382193.2 A8MXZ9

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152132
Hom.:
0
Cov.:
32
show subpopulations
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:
0.00
GnomAD4 exome
AF:
0.00000412
AC:
6
AN:
1456496
Hom.:
0
AF XY:
0.00000691
AC XY:
5
AN XY:
723952
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000451
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152132
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74318
show subpopulations
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:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:16Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 4 Pathogenic:5
Oct 26, 2017
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 08, 2022
Baylor Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 31, 2017
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 24, 2021
Clinical Genetics Laboratory, Region Ostergotland
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PS4, PM2, PM4 -

Apr 24, 2023
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:3Uncertain:1
-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 21, 2017
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3407_3409delACT variant of uncertain significance in the MYBPC3 gene has been reported previously in two individuals with HCM; however, no detailed clinical or segregation data were provided (Sequeira et al., 2013; Murphy et al., 2016). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This three nucleotide deletion results in elimination of a tyrosine residue at position 1136, and does not result in a shift in reading frame. Tyrosine at this position is conserved in mammals and in silio analysis predicts this deletion to be damaging to the protein structer/function. However, the c.3407_3409delACT variant lacks sufficient evidence, including observation in a significant number of affected inidividuals, segregation studies, and functional characterization, that would further clarify its potential pathogenicity. -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy Pathogenic:3
Nov 13, 2023
All of Us Research Program, National Institutes of Health
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3407_3409del (p.Tyr1136del) variant of the MYBPC3 gene leads to the deletion of 1 amino acid of the MYBPC3 protein (p.Tyr1136del), but otherwise preserves the integrity of the reading frame. This variant has been observed in individuals with hypertrophic cardiomyopathy (PMID: 24835277, 31323898, 29875424, 23508784, 33495596, 26914223, 30685992, 31513939, 33673806). This variant is not present in the general population by the Genome Aggregation Database (gnomAD). Therefore the c.3407_3409del (p.Tyr1136del) variant of the MYBPC3 gene is classified as likely pathogenic. -

Dec 27, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant, c.3407_3409del, results in the deletion of 1 amino acid(s) of the MYBPC3 protein (p.Tyr1136del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hypertrophic cardiomyopathy (PMID: 23508784, 26914223, 30685992, 31513939, 33673806, 35626289; internal data). ClinVar contains an entry for this variant (Variation ID: 181102). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Oct 31, 2018
Center for Human Genetics, University of Leuven
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Left ventricular noncompaction 10 Pathogenic:1
Dec 08, 2022
Baylor Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiomyopathy Pathogenic:1
Apr 21, 2023
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Brugada syndrome Pathogenic:1
-
Institute of Human Genetics, Medical University Innsbruck
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Primary familial hypertrophic cardiomyopathy Pathogenic:1
Oct 29, 2015
Blueprint Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1
Nov 27, 2023
Ambry Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3407_3409delACT variant (also known as p.Y1136del) is located in coding exon 31 of the MYBPC3 gene. This variant results from an in-frame ACT deletion at nucleotide positions 3407 to 3409. This results in the in-frame deletion of a tyrosine at codon 1136. This alteration has been reported in several individuals with hypertrophic cardiomyopathy (HCM) (Lopes LR et al. J Med Genet, 2013 Apr;50:228-39; Sequeira V et al. Circ. Res., 2013 May;112:1491-505; Witjas-Paalberends ER et al. Cardiovasc. Res., 2014 Jul;103:248-57; Murphy SL et al. J Cardiovasc Transl Res, 2016 Apr;9:153-61; Dorsch LM et al. Cells, 2019 07;8:[ePub ahead of print]; Mazzarotto F et al. Genet Med, 2019 02;21:284-292; Nagyova E et al. Bratisl Lek Listy, 2019 Oct;120:46-51; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754; Harper AR et al. Nat Genet, 2021 02;53:135-142; Hathaway J et al. BMC Cardiovasc Disord, 2021 03;21:126; Tadros R et al. Nat Genet, 2021 02;53:128-134; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not specified Uncertain:1
Jun 12, 2017
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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.

Other links and lift over

dbSNP: rs730880674; hg19: chr11-47354445; API