Submissions for variant NM_020778.5(ALPK3):c.61_62delinsT (p.Gly21fs)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002366962	SCV002661761	pathogenic	Cardiovascular phenotype	2023-04-03	criteria provided, single submitter	clinical testing	The c.667_668delGGinsT pathogenic mutation, located in coding exon 1 of the ALPK3 gene, results from the deletion of two nucleotides and insertion of one nucleotide causing a translational frameshift with a predicted alternate stop codon (p.G223Sfs*88). 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.
GeneDx	RCV003098326	SCV003195103	likely pathogenic	not provided	2023-01-24	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 significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV003098326	SCV004477539	pathogenic	not provided	2024-11-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly223Serfs*88) 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). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has not been reported in the literature in individuals affected with ALPK3-related conditions. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004785622	SCV005398148	pathogenic	Cardiomyopathy, familial hypertrophic 27	2024-10-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.5, 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) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (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. Monoallelic NMD-predicted ALPK3 variants have also been reported in adults with hypertrophic cardiomyopathy with age-dependent penetrance (PMID: 32480058, 34263907, 38356193). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported twice as pathogenic and once as likely 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
North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust	RCV004785622	SCV005627604	pathogenic	Cardiomyopathy, familial hypertrophic 27	2024-10-03	criteria provided, single submitter	clinical testing	PM2_Mod PVS1_VStr