Hypertrophic cardiomyopathy

Gene: ACTN2

Green List (high evidence)

Submitted on behalf of the GMS Cardiology specialist group. This gene did not achieve a consensus Green rating; however, the group agreed that the existing evidence (published and in-house data) was sufficient to support inclusion in this panel.

Created: 9 Dec 2019, 1:19 p.m. | Last Modified: 9 Dec 2019, 1:19 p.m.

Panel Version: 1.93

I don't know

Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Amber on this panel.

Created: 2 Dec 2019, 11:26 a.m. | Last Modified: 2 Dec 2019, 11:26 a.m.

Panel Version: 1.81

I don't know

Possible rare cause of HCM. Not currently tested on Manchester HCM panel.

Created: 27 Sep 2019, 1:12 p.m. | Last Modified: 27 Sep 2019, 1:12 p.m.

Panel Version: 1.74

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Cardiomyopathy, dilated, 1AA, with or without LVNC 612158; Cardiomyopathy, hypertrophic, 23, with or without LVNC 612158

Publications

• 20022194
• 27287556

I don't know

On current CGGL Royal Brompton diagnostic panel, but only VUs reported so far. some limited evidence of LVH phenotype associated, so appropriate for HCm panel due to overlapping phenotype. Listed as definite cardiomyopathy gene by ClinGen.

Created: 18 Sep 2019, 1:07 p.m. | Last Modified: 18 Sep 2019, 1:07 p.m.

Panel Version: 1.74

Variants in this GENE are reported as part of current diagnostic practice

I don't know

Cardiomyopathy, hypertrophic, 23, with or without LVNC (612158)

Created: 25 Mar 2019, 4:30 p.m.

Reported to segregate in relatively large pedigrees, but LOD score <3. Moderate evidence: 28082330. Classified as a core HCM gene: 29567486

Created: 25 Mar 2019, 4:27 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Variants in this GENE are reported as part of current diagnostic practice

I don't know

This gene was part of an initial gene list collated by Matthew Edwards Royal Brompton Hospital sent 16th Jan 2019 on behalf of the London South GLH for review by the GMS Cardiology Specialist Group. Only gene symbol from the Royal Brompton gene panel was provided - suggested initial gene rating and evidence for inclusion not provided with the list.

Created: 20 Feb 2019, 2:17 p.m.

I don't know

Amber gene. For discussion. A very small number of missense variant (n=2) have been show to segreate with atypical cardiac phenotypes-not specifically HCM. ClinGen have labelled this an intrinsic cardiomyoapthy gene. Missense variants (other than the 2 reported in the literature with segregation) are generally uninterpretable and so classified as VUS. In previous case vs control analyses (Walsh et al PMID -27532257) we did not detect a burden of rare missense variants in this gene in cases (HCM or DCM) compared to reference cohorts. However we have emerging evidence from our cohort that heterozygous LOF(including large scale deletions and duplications) variants in this gene may be pathogenic. At present not a Green gene but perhaps worthy of further investigation.

Created: 17 Jan 2019, 5:06 p.m.

Only two variants (p.Ala119Thr and p.Met228Thr) described with significant cosegregation evidence. Phenotypes inc. HCM, LVNC, and arrhythmias. Incomplete penetrance described.

Created: 6 Jan 2016, 5:11 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• Publications supporting role of this gene in HCM - [PMID: 25224718
• PMID: 25173926
• PMID: 20022194

Variants in this GENE are reported as part of current diagnostic practice