Submissions for variant NM_025144.4(ALPK1):c.710C>T (p.Thr237Met)

dbSNP: rs1052954321

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Undiagnosed Diseases Network, NIH	RCV001263103	SCV001245584	pathogenic	Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome	2019-11-07	criteria provided, single submitter	clinical testing	Observed in proband and similarly affected father and paternal uncle. The variant detected in this family has been reported in the literature in six other families with the same condition (PMID: 30967659, PMID: 31053777).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001389989	SCV001591556	pathogenic	not provided	2020-06-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect ALPK1 protein function (PMID: 30967659). This sequence change replaces threonine with methionine at codon 237 of the ALPK1 protein (p.Thr237Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with ROSAH syndrome (PMID: 30967659, 31053777). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 619031).
CeGaT Center for Human Genetics Tuebingen	RCV001389989	SCV002062554	pathogenic	not provided	2021-10-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001263103	SCV002769505	pathogenic	Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome	2023-07-16	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: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with ROSAH syndrome (MIM#614979) (PMIDs: 30967659, 35868845). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - This variant is known to have variable expressivity even within families (PMIDs: 30967659, 31939038, 35868845). (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is located in the annotated ligand binding domain (PMID: 35868845). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is a recurrent variant in this gene and it has been reported in multiple families of various ethnicities with ROSAH syndrome (ClinVar, PMIDs: 30967659, 31053777, 31939038). (SP) 0901 - This variant has strong evidence for segregation with disease in five unrelated families (PMID: 30967659). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Overexpression of mutant protein in HeLa cells showed increased multinucleated cells. In addition, there was decreased number of ciliated cells in fibroblasts and a significant decrease in assembly of primary cilia in the affected patients carrying this variant compared with control (PMID: 30967659). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
PreventionGenetics, part of Exact Sciences	RCV003947961	SCV004759645	pathogenic	ALPK1-related disorder	2024-02-11	criteria provided, single submitter	clinical testing	The ALPK1 c.710C>T variant is predicted to result in the amino acid substitution p.Thr237Met. This variant has been reported in multiple unrelated families with ROSAH syndrome (see for example - Fardeau et al. 2022. PubMed ID: 36543582; Kozycki et al. 2022. PubMed ID: 35868845). Functional studies found this variant impacts protein function (Kozycki et al. 2022. PubMed ID: 35868845). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant is interpreted as likely pathogenic/pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/619031/). This variant is interpreted as pathogenic.
Ambry Genetics	RCV004629319	SCV005129758	pathogenic	Inborn genetic diseases	2024-04-11	criteria provided, single submitter	clinical testing	The c.710C>T (p.T237M) alteration is located in exon 9 (coding exon 7) of the ALPK1 gene. This alteration results from a C to T substitution at nucleotide position 710, causing the threonine (T) at amino acid position 237 to be replaced by a methionine (M). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been observed de novo in multiple individuals and to segregate with disease in multiple families with clinical features consistent with ALPK1-associated ROSAH syndrome (Williams, 2019). This amino acid position is well conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Children's Medical Research Institute, University of Sydney	RCV001263103	SCV000886402	likely pathogenic	Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome	2019-01-17	no assertion criteria provided	research	The heterozygous Thr237Met variant in ALPK1 has been found in a three generation Australian family, segregates with disease and studies of primary cilium function indicate functional abnormality. Affected individuals have retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis and migraine headache which is called ROSAH syndrome.
OMIM	RCV001263103	SCV001441183	pathogenic	Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome	2023-09-01	no assertion criteria provided	literature only