rs397516047

Positions:

• chr11-47350086-GAC-G

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.431_432delGT​(p.Gly144fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000711 in 1,406,688 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.228

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 11-47350086-GAC-G is Pathogenic according to our data. Variant chr11-47350086-GAC-G is described in ClinVar as [Pathogenic]. Clinvar id is 42749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47350086-GAC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.431_432delGT	p.Gly144fs	frameshift_variant	4/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.431_432delGT	p.Gly144fs	frameshift_variant	4/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.431_432delGT	p.Gly144fs	frameshift_variant	4/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.431_432delGT		non_coding_transcript_exon_variant	4/27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1406688 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 694692

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: 9.23e-7

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

Hypertrophic cardiomyopathy 4 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein. (P) Exon 4 of 35. 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. (P) All / most frameshift / nonsense variants are reported as Pathogenic / Likely Pathogenic (ClinVar, Decipher). 0803 - Low previous evidence of pathogenicity in unrelated individuals. (P) There appears to be only one previously reported patient with this variant. (ClinVar, also shown in the Atlas of Cardiac Genetic variation (www.cardiodb.org), and described in Walsh, R. et al. (2017)). 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jul 07, 2023	- -

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 18, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 42749). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25611685, 27532257). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly144Alafs*8) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 10, 2012	The Gly144fs variant in MYBPC3 has not been reported in the literature nor previ ously identified by our laboratory out of >3500 individuals (>2100 Caucasian; LM M unpublished data). This low frequency supports a pathogenic role. This framesh ift variant is predicted to alter the protein?s amino acid sequence beginning at position 144 and lead to a premature termination codon 8 amino acids downstream . This alteration is then predicted to lead to a truncated or absent protein. He terozygous loss of function of function of the MYBPC3 gene is an established dis ease mechanism in HCM patients. In summary, this variant meets our criteria to b e classified as pathogenic (http://pcpgm.partners.org/LMM). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397516047; hg19: chr11-47371637;