Submissions for variant NM_002637.4(PHKA1):c.3043C>T (p.Arg1015Cys)

gnomAD frequency: 0.00001  dbSNP: rs782191011

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000427839	SCV000528506	likely benign	not specified	2016-06-20	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Mayo Clinic Laboratories, Mayo Clinic	RCV000675443	SCV000801124	uncertain significance	not provided	2019-04-29	criteria provided, single submitter	clinical testing
Invitae	RCV001861570	SCV002124578	uncertain significance	Glycogen storage disease IXd	2023-01-31	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 386748). This variant has not been reported in the literature in individuals affected with PHKA1-related conditions. This variant is present in population databases (rs782191011, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1015 of the PHKA1 protein (p.Arg1015Cys).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000675443	SCV001553931	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PHKA1 p.Arg1015Cys variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs782191011), ClinVar (classified as likely benign by GeneDx and Mayo Clinic Genetic Testing Laboratories), Cosmic (FATHMM prediction of pathogenic; score 0.78). The variant was also identified in control databases in 11 of 176599 chromosomes at a frequency of 0.000062 (Genome Aggregation Database Feb 27, 2017) and was observed in the following populations: South Asian in 7 of 17879 chromosomes (freq: 0.000392), East Asian in 1 of 13487 chromosomes (freq: 0.000074) and European (non-Finnish) in 3 of 77980 chromosomes (freq: 0.000038), while the variant was not observed in the African, Latino, Ashkenazi Jewish, European (Finnish) and Other populations. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg1015 residue is conserved across mammals and other organisms, and 4 out of 5 computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster) suggest that the R variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.