Submissions for variant NM_020778.5(ALPK3):c.4391del (p.Asn1464fs)

dbSNP: rs1450218521

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825510	SCV000966818	likely pathogenic	Hypertrophic cardiomyopathy	2018-03-19	criteria provided, single submitter	clinical testing	The p.Asn1666fs variant in ALPK3 has not been previously reported in individuals with cardiomyopathy, but has been identified in 1/111490 European chromosomes b y the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Th is variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 1666 and leads to a premature termination co don 14 amino acids downstream. This alteration is then predicted to lead to a tr uncated or absent protein. Biallelic loss-of-function (LOF) variants in the ALPK 3 gene have been reported in multiple individuals and in a mouse model with card iomyopathy (HCM or mixed HCM/DCM; Almomani 2016, Phelan 2016, Van Sligtenhorst 2 012). In summary, although additional studies are required to fully establish it s clinical significance, the p.Asn1666fs variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PVS1_Strong.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001701446	SCV002161704	pathogenic	not provided	2024-09-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn1666Thrfs*14) 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 (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 32480058). ClinVar contains an entry for this variant (Variation ID: 666961). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001701446	SCV002568769	likely pathogenic	not provided	2022-07-19	criteria provided, single submitter	clinical testing	Frameshift 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; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30847666, 33076350, 32480058)
Ambry Genetics	RCV002336730	SCV002640453	pathogenic	Cardiovascular phenotype	2022-06-06	criteria provided, single submitter	clinical testing	The c.4997delA pathogenic mutation, located in coding exon 10 of the ALPK3 gene, results from a deletion of one nucleotide at nucleotide position 4997, causing a translational frameshift with a predicted alternate stop codon (p.N1666Tfs*14). This variant co-occurred with a missense variant in ALPK3 in a proband with hypertrophic cardiomyopathy (HCM), and has been detected in cohorts referred for HCM and arrhythmogenic right ventricular cardiomyopathy genetic testing (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Herkert JC et al. Am Heart J, 2020 07;225:108-119). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
KardioGenetik, Herz- und Diabeteszentrum NRW	RCV004669149	SCV005094549	likely pathogenic	Cardiomyopathy, familial hypertrophic 27	2024-06-21	criteria provided, single submitter	clinical testing	Detected without any additional variants. ACMG-criteria applied: PVS1, PM2_supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005240625	SCV005884872	pathogenic	Cardiomyopathy	2024-12-27	criteria provided, single submitter	clinical testing	Variant summary: ALPK3 c.4391delA (p.Asn1464ThrfsX14) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 251210 control chromosomes (gnomAD). c.4391delA has been reported in the literature in individuals affected with Cardiomyopathy (van Lint_2019, Herkert_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32480058, 30847666). ClinVar contains an entry for this variant (Variation ID: 666961). Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics, Academic Medical Center	RCV001701446	SCV001922574	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001701446	SCV001963378	pathogenic	not provided		no assertion criteria provided	clinical testing