Hypertrophic cardiomyopathy

Gene: ALPK3

Green List (high evidence)

Summary of evidence considered by ClinGen expert panel for ALPK3 and AD HCM gene-disease validity

Created: 23 Apr 2025, 12:32 p.m. | Last Modified: 23 Apr 2025, 12:32 p.m.

Panel Version: 4.21

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Hypertrophic cardiomyopathy

Publications

• 40255155

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

Green List (high evidence)

Both biallelic and monoallelic ALPK3 variants are associated with hypertrophic cardiomyopathy (MONDO:0005045). The ClinGen Hereditary Cardiovascular Disease Expert Panel has classified this association as Definitive for autosomal recessive inheritance (https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6312d79f-df12-4ec6-8ce6-0f38f19e617d-2022-02-09T170000.000Z?page=1&size=25&search=) and Strong for Autosomal dominant inheritance (https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ace85164-0b70-46a2-ac6b-253088f4514d-2023-12-19T010000.000Z?page=1&size=25&search=)

Created: 13 Aug 2024, 4:18 p.m. | Last Modified: 13 Aug 2024, 4:18 p.m.

Panel Version: 4.16

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Green List (high evidence)

The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 11 Dec 2025, 4:05 p.m. | Last Modified: 11 Dec 2025, 4:05 p.m.

Panel Version: 5.22

The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.

Created: 30 Jan 2023, 3:21 p.m. | Last Modified: 30 Jan 2023, 3:21 p.m.

Panel Version: 3.3

Green List (high evidence)

Three publications (32480058; 34263907; 35583889) have now established that monoallelic ALPK3 truncating (LOF) variants are enriched in cases vs controls (including gnomAD and UKBB; OR 13-16). Two publications have described co-segregation for heterozygous ALPK3tv, including one (34263907) with 44 ALPK3tv patients from a total cohort of ~2800 and another case report in 1 large family (33191771). Overall, the available data provide evidence for heterozygous causality with late/incomplete penetrance (similarly to other established HCM causal genes) and a pediatric more severe presentation for biallelic forms (including extra-cardiac/syndromic features).

Created: 23 May 2022, 8:08 a.m. | Last Modified: 23 May 2022, 8:08 a.m.

Panel Version: 2.38

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Hypertrophic Cardiomyopathy

Publications

• PMID: 34263907
• 35583889

Green List (high evidence)

Further work recently published involving genotyping of 2800 HCM patients (PMID 32480058). Overall 44 HCM patients carrying heterozygous truncations identified (1.56% overall). OR 16. Segregation in 7 families described - LOD 2.99.
Overall decent evidence for the pathogenicity of heterozygous truncations in HCM.

Created: 8 Oct 2021, 4:10 p.m. | Last Modified: 8 Oct 2021, 4:10 p.m.

Panel Version: 2.26

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Hypertrophic Cardiomyopathy

Publications

• 32480058

Green List (high evidence)

As mentioned - should be BOTH biallelic and monoallelic. Still not updated.

Created: 11 Feb 2025, 11:39 a.m. | Last Modified: 11 Feb 2025, 11:39 a.m.

Panel Version: 4.20

As described by Luis Lopes, should be BOTH monoallelic and biallelic on this panel.

Created: 28 Apr 2024, 5:20 p.m. | Last Modified: 28 Apr 2024, 5:20 p.m.

Panel Version: 4.7

>42 individuals with truncating ALPK3 and HCM are described in PMID: 32480058. OR = 16 for developing HCM with ALPK3tv, so should be considered green for monoallelic inheritance.

Created: 21 Jul 2021, 11:57 a.m. | Last Modified: 21 Jul 2021, 11:57 a.m.

Panel Version: 2.22

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Hypertrophic cardiomyopathy

Publications

• PMID: 32480058

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

Comment on publications: New publications added.

Created: 24 May 2022, 7:29 a.m. | Last Modified: 24 May 2022, 7:29 a.m.

Panel Version: 2.39

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed.

Created: 3 Mar 2022, 11:45 a.m. | Last Modified: 3 Mar 2022, 11:45 a.m.

Panel Version: 2.33

Comment on mode of inheritance: MOI has been changed from "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" to "BIALLELIC, autosomal or pseudoautosomal".

All the published cases of affected individuals have homozygous variants in this gene. However, family members who are heterozygous for the ALPK3 variants either show no cardiac phenotype or have later-onset cardiomyopathy or an atypical distribution of hypertrophy (PMID: 26846950, 30046096, 2710685, 32480058). PMID: 32480058 found that some individuals with heterozygous variants in ALPK3 are diagnosed with HCM when they are adults. The paper suggests that LoF ALPK3 variants are enriched in adults with cardiomyopathy and may contribute to their cardiomyopathy.

More evidence is needed for heterozygous variants in ALPK3 contributing to disease, so therefore the change of MOI. The inclusion of heterozygous variants of ALPK3 will be reviewed at the next panel review.

Created: 11 Nov 2020, 3:51 p.m. | Last Modified: 11 Nov 2020, 3:51 p.m.

Panel Version: 2.14

Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to support a gene-disease assocation for it to be Green. This gene will be promoted to Green at the next panel review.

Created: 5 Oct 2020, 12:09 p.m. | Last Modified: 5 Oct 2020, 12:09 p.m.

Panel Version: 2.11

Comment on publications: PMID: 28630369. An additional case. Non-consanguineous family of Turkish decent. Fetus was homozgyous for variant and died at 30 weeks gestation. Heterozygous family members had normal cardiac function. Fetus also had dysmorphic facial features.

PMID: 30046096. An additional case. A consanguineous family of Tunisian decent. 3 year old affected with mixed HCM/DCM and dysmorphic features.

PMID: 31074094. An additional case. A family with 6 affected individuals.

PMID: 21441111. KO mouse model that replicates the human disease phenotype

Created: 5 Oct 2020, 11:52 a.m. | Last Modified: 5 Oct 2020, 11:52 a.m.

Panel Version: 2.10

Green List (high evidence)

Assessed as Strong by ClinGen (ALPK3-HCM)

4 consanguineous families with ALPK3 biallelic pathogenic variants were identified in 2 papers. 3 families are reported in Alomani (2015) (26846950) and 1 in Phelan (2016) with accompanying functional evidence (27106955). ALPK3 knock out mice develop cardiomyopathy (DCM and HCM) Van Sligtenhorst (2012).

A case series of 19 paeditric cardiomyopathy cases with ALPK3 pathogeic variants concluded: Biallelic damaging ALPK3 variants cause pediatric cardiomyopathy manifested by DCM transitioning to hypertrophy, often with poor contractile function. Additional extracardiac features occur in most patients, including musculoskeletal abnormalities and cleft palate. Heterozygous LoF ALPK3 variants are enriched in adults with cardiomyopathy and may contribute to their cardiomyopathy. Adults with ALPK3 LoF variants therefore warrant evaluations for cardiomyopathy.
Sources: Expert list

Created: 30 Jul 2020, 3:56 a.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Hypertrophic cardiomyopathy

Publications

• 26846950
• 27106955
• 32480058

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