11-47342909-AGG-AG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000256.3(MYBPC3):c.1377del(p.Leu460TrpfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,200 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P459P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.585

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-47342909-AG-A is Pathogenic according to our data. Variant chr11-47342909-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 188548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47342909-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.1377del	p.Leu460TrpfsTer6	frameshift_variant	16/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1377del	p.Leu460TrpfsTer6	frameshift_variant	16/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.1377del	p.Leu460TrpfsTer6	frameshift_variant	15/34	5		A2
MYBPC3	ENST00000544791.1	c.1377del	p.Leu460TrpfsTer6	frameshift_variant, NMD_transcript_variant	16/27	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460200 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726242

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jun 07, 2021

This variant (also known as Pro459fs) results in the deletion of 1 nucleotide in exon 15 of the MYBPC3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in seven Chinese individuals affected with hypertrophic cardiomyopathy (PMID: 21165360, 23283745, 23711808, 26090888). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 03, 2017

The c.1377delC pathogenic variant, also denoted as P459fs due to alternate nomenclature, has been previously reported in six unrelated individuals with HCM, and five of these individuals were noted to be of Chinese ancestry (Lin et al., 2010; Zou et al., 2013; Liu et al., 2015; Walsh et al., 2017). It has also has been shown to segregate with HCM in one affected relative from one family (Lin et al., 2010). Additionally, c.1377delC is classified as a likely pathogenic variant in ClinVar by a different clinical laboratory in association with HCM (ClinVar SCV000219705.2 ; Landrum et al., 2016). This variant causes a shift in reading frame starting at codon leucine 460, changing it to a tryptophan, and creating a premature stop codon at position 6 of the new reading frame, denoted p.Leu460TrpfsX6. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Furthermore, multiple other frameshift variants in the MYBPC3 gene have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014). Finally, the c.1377delC variant has not been observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 08, 2023

This sequence change creates a premature translational stop signal (p.Leu460Trpfs*6) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 21165360, 23283745, 23711808, 26090888). It has also been observed to segregate with disease in related individuals. This variant is also known as Pro459fs. ClinVar contains an entry for this variant (Variation ID: 188548). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 23, 2022

The c.1377delC pathogenic mutation, located in coding exon 16 of the MYBPC3 gene, results from a deletion of one nucleotide at nucleotide position 1377, causing a translational frameshift with a predicted alternate stop codon (p.L460Wfs*6). This variant (also referred to as Pro459fs) has been detected in several individuals reported to have hypertrophic cardiomyopathy (HCM) and has been reported to segregate with disease in families (Lin J et al. Can J Cardiol, 2010 Dec;26:518-22; Zou Y et al. Mol Biol Rep, 2013 Jun;40:3969-76; Liu X et al. Sci Rep, 2015 Jun;5:11411; Helms AS et al. Circ Genom Precis Med, 2020 Oct;13:396-405; Wu G et al. Circ Genom Precis Med, 2021 Oct;14:e003401; Wang Y et al. Stem Cell Res, 2021 Nov;57:102594; Liu W et al. Clin Chim Acta, 2021 Sep;520:43-52). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

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: rs786204339; hg19: chr11-47364460;