rs863225269

Variant names:

• chr14-23392969-T-TG
• rs863225269
• NM_002471.4:c.3193dupC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_002471.4(MYH6):​c.3193dupC​(p.Gln1065ProfsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH6 NM_002471.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.65
• Publications: 1 publications found

Genes affected

MYH6 (HGNC:7576): (myosin heavy chain 6) Cardiac muscle myosin is a hexamer consisting of two heavy chain subunits, two light chain subunits, and two regulatory subunits. This gene encodes the alpha heavy chain subunit of cardiac myosin. The gene is located approximately 4kb downstream of the gene encoding the beta heavy chain subunit of cardiac myosin. Mutations in this gene cause familial hypertrophic cardiomyopathy and atrial septal defect 3. [provided by RefSeq, Feb 2017]

MYH6 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy 14

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine
• Keppen-Lubinsky syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Illumina
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• atrial septal defect 3

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 14-23392969-T-TG is Pathogenic according to our data. Variant chr14-23392969-T-TG is described in ClinVar as Pathogenic. ClinVar VariationId is 217832.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH6	NM_002471.4	c.3193dupC	p.Gln1065ProfsTer10	frameshift_variant	Exon 24 of 39	ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9	c.3193dupC	p.Gln1065ProfsTer10	frameshift_variant	Exon 24 of 39	5	NM_002471.4	ENSP00000386041.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy 1 Pathogenic:1

Apr 21, 2015

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This MYBPC3 Lys1065fs variant results from a single bp insertion, which is predicted to cause a frameshift at codon 1065 and premature stop codon 12 amino acids downstream. This alteration is predicted to lead to a truncated or absent protein. This variant is absent from population datasets including the 1000 genomes project (http://www.1000genomes.org/) and the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). MYBPC3 Lys1065fs has been identified in multiple unrelated HCM cases (see references). We have identified the this variant in one male HCM patient. Familial segregation revealed his affected nephew to also carried this variant. Based on the absence of this variant in the general population, observations of the variant in multiple unrelated HCM patients reported in the literature, and that loss-of-function variants in MYBPC3 are an established mechanism of disease in HCM, we classify MYBPC3 Lys1065fs as "pathogenic". -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6
Mutation Taster		=20/180	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs863225269; hg19: chr14-23862178;