Submissions for variant NM_020778.5(ALPK3):c.4213C>T (p.Arg1405Ter)

gnomAD frequency: 0.00001  dbSNP: rs1344615174

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001545066	SCV001764321	likely pathogenic	not provided	2025-03-26	criteria provided, single submitter	clinical testing	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; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001545066	SCV002242720	pathogenic	not provided	2024-11-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1607*) 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 0.006%). This variant has not been reported in the literature in individuals affected with ALPK3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1186088). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331180	SCV004039486	pathogenic	Cardiomyopathy	2023-08-14	criteria provided, single submitter	clinical testing	Variant summary: ALPK3 c.4213C>T (p.Arg1405X) 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 1.2e-05 in 251426 control chromosomes. To our knowledge, no occurrence of c.4213C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004594353	SCV005086798	pathogenic	Cardiomyopathy, familial hypertrophic 27	2023-07-17	criteria provided, single submitter	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) 0106 - This gene is associated with autosomal recessive disease. However, emerging evidence supports autosomal dominant inheritance in adults with age-dependent penetrance (PMIDs: 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 (v2) <0.01 (3 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic (DECIPHER, PMID: 34263907). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and as pathogenic (ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics	RCV004995940	SCV005610841	pathogenic	Cardiovascular phenotype	2024-08-23	criteria provided, single submitter	clinical testing	The p.R1607* pathogenic mutation (also known as c.4819C>T), located in coding exon 10 of the ALPK3 gene, results from a C to T substitution at nucleotide position 4819. This changes the amino acid from an arginine to a stop codon within coding exon 10. This variant has been detected in an individual from a cardiomyopathy cohort, and in an individual with features consistent with hypertrophic cardiomyopathy (Akinrinade O et al. J Cardiovasc Transl Res, 2023 Dec;16:1287-1302; Ambry internal data). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.