rs730880674

chr11-47332894-AAGT-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM4_Supporting PP5

The NM_000256.3(MYBPC3):c.3407_3409del(p.Tyr1136del) variant causes a 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). Synonymous variant affecting the same amino acid position (i.e. Y1136Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:16 U:2
• Conservation: PhyloP100: 8.93

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 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: {Likely_pathogenic=10, Uncertain_significance=2, Pathogenic=2}. Variant chr11-47332894-AAGT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.3407_3409del	p.Tyr1136del	inframe_deletion	31/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3407_3409del	p.Tyr1136del	inframe_deletion	31/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.3407_3409del	p.Tyr1136del	inframe_deletion	30/34	5		A2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152132 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: 0.00

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

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

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:16 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy 4 Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 08, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Apr 24, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 26, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Region Ostergotland	Feb 24, 2021	PS4, PM2, PM4 -

not provided Pathogenic:3 Uncertain:1

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2017	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. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Hypertrophic cardiomyopathy Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 13, 2023	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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 181102). This variant has been observed in individuals with hypertrophic cardiomyopathy and/or MYBPC3-related conditions (PMID: 23508784, 26914223, 30685992, 31513939, 33673806; Invitae). This variant is not present in population databases (gnomAD no frequency). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 13, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Oct 31, 2018	- -

Left ventricular noncompaction 10 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 08, 2022

- -

Cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Apr 21, 2023

- -

Brugada syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Medical University Innsbruck

-

- -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Oct 29, 2015

- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 27, 2023

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

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jun 12, 2017

- -

Computational scores

Source: dbNSFP v4.3

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: rs730880674; hg19: chr11-47354445;