Genetic Variant ALPK3:p.Arg1059* (chr15-84857913-C-T) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_020778.5(ALPK3):c.3175C>T(p.Arg1059*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000072 in 1,610,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

ALPK3
NM_020778.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 2.66

Variant links:

Genes affected

ALPK3 (HGNC:17574): (alpha kinase 3) Predicted to enable ATP binding activity; protein serine kinase activity; and protein serine/threonine kinase activity. Predicted to be involved in cardiac muscle cell development. Predicted to be active in nucleus. Implicated in hypertrophic cardiomyopathy. [provided by Alliance of Genome Resources, Apr 2022]

ALPK3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 15-84857913-C-T is Pathogenic according to our data. Variant chr15-84857913-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 488984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-84857913-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPK3	NM_020778.5 link	c.3175C>T	p.Arg1059*	stop_gained	Exon 6 of 14	ENST00000258888.6	NP_065829.4	Q96L96

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPK3	ENST00000258888.6 link	c.3175C>T	p.Arg1059*	stop_gained	Exon 6 of 14	1	NM_020778.5	ENSP00000258888.6		Q96L96

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000416

AC:

AN:

240334

Hom.:

AF XY:

0.0000305

AC XY:

AN XY:

131030

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000333

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000839

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000754

AC:

110

AN:

1458712

Hom.:

Cov.:

AF XY:

0.0000717

AC XY:

AN XY:

725530

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000891

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cardiomyopathy, familial hypertrophic 27

Pathogenic:5

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial hypertrophic cardiomyopathy 27 (MIM#618052). (I) 0108 - This gene is associated with both recessive and dominant disease (PMID: 34263907). (I) 0112 - The condition associated with this gene has incomplete penetrance. Age-dependent penetrance has been observed in the autosomal dominant condition (PMID: 32480058, 34263907). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (10 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Other variants predicted to cause NMD have been reported in ClinVar as pathogenic in individuals with cardiomyopathy. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported as pathogenic in patients with cardiomyopathy (ClinVar, PMID: 26846950). (SP) 0902 - This variant has moderate evidence for segregation with disease. The variant has also been shown to segregate with disease in three affected siblings from one family (PMID: 26846950). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Mar 13, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Predicted Consequence/Location: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000488984 /PMID: 26846950). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Oct 03, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 23, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ALPK3 c.3175C>T, p.Arg1059Ter variant (rs749465164) is reported homozygous in the literature in a family with severe pediatric cardiomyopathy and heterozygous in the asymptomatic parents (Almomani 2016). This variant is reported in ClinVar (Variation ID: 488984). This variant is found in the non-Finnish European population with an allele frequency of 0.008% (9/107310 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Almomani R et al. Biallelic Truncating Mutations in ALPK3 Cause Severe Pediatric Cardiomyopathy. J Am Coll Cardiol. 2016 Feb 9;67(5):515-25. PMID: 26846950. -

Dec 31, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ALPK3: PVS1, PM2, PM3 -

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg1261*) in the ALPK3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALPK3 are known to be pathogenic (PMID: 21441111, 26846950, 27106955, 34263907). This variant is present in population databases (rs749465164, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with ALPK3-related conditions (PMID: 26846950). ClinVar contains an entry for this variant (Variation ID: 488984). For these reasons, this variant has been classified as Pathogenic. -

Mar 24, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in the homozygous state, as p.(R1261*) due to use of alternate nomenclature, in three children from consanguineous parents with features of cardiomyopathy; the unaffected father and one unaffected sibling were heterozgyous for this variant (PMID: 26846950, 32480058); Has also been observed in heterozygous state in patients with features of hypertrophic cardiomyopathy but detailed clinical information was not specified (PMID: 39036505, 34263907); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27106955, 28630369, 32480058, 31216405, 34263907, 39036505, 26846950, 29661763) -

Neurodevelopmental disorder

Pathogenic:1

Jan 19, 2021

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Pathogenic:1

Jul 26, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1261* pathogenic mutation (also known as c.3781C>T), located in coding exon 6 of the ALPK3 gene, results from a C to T substitution at nucleotide position 3781. This changes the amino acid from an arginine to a stop codon within coding exon 6. This variant has been reported in the homozygous state in three siblings of unaffected, consanguineous parents. Two siblings were diagnosed with severe cardiomyopathy and hydrops fetalis in utero, and one was diagnosed with severe concentric left ventricular hypertrophy at birth. An unaffected sibling and the father were heterozygous for the variant (Almomani R et al. J. Am. Coll. Cardiol., 2016 Feb;67:515-25). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

ALPK3-related disorder

Pathogenic:1

Jul 13, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ALPK3 c.3781C>T variant is predicted to result in premature protein termination (p.Arg1261*). This variant has been reported in the homozygous state in individuals with congenital cardiomyopathy (see for example - Almomani et al. 2016. PubMed ID: 26846950; Table S2, van Velzen et al. 2018. PubMed ID: 29661763). This variant is reported in 0.0084% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-85401144-C-T). Nonsense variants in ALPK3 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Benign

0.17

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.46

Vest4

0.022

GERP RS

0.23

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over