Submissions for variant NM_000292.3(PHKA2):c.3614C>T (p.Pro1205Leu)

dbSNP: rs137852288

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000011277	SCV000917993	pathogenic	Glycogen storage disease IXa1	2018-06-27	criteria provided, single submitter	clinical testing	Variant summary: PHKA2 c.3614C>T (p.Pro1205Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 200197 control chromosomes (gnomAD). The variant, c.3614C>T, has been reported in the literature in multiple individuals both in heterozygote females and hemizygote males affected with Glycogen storage disease, type IXa1. Cho_2013 reports the variant in a female Chinese patient accompanied with a skewed X-chromosome inactivation, therefore, explaining the phenotypic representation in some females. Achouitar_2011 suggests the variant to be a Dutch founder mutation. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000011277	SCV000940761	pathogenic	Glycogen storage disease IXa1	2022-10-05	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 10531). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PHKA2 protein function. This missense change has been observed in individuals with glycogen storage disease or phosphorylase kinase (PHK) deficiency (PMID: 7847371, 9870210, 21646031, 21911307, 24055370, 25266922, 28468868). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1205 of the PHKA2 protein (p.Pro1205Leu).
CeGaT Center for Human Genetics Tuebingen	RCV001091309	SCV001247263	pathogenic	not provided	2019-05-01	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000011277	SCV001852724	pathogenic	Glycogen storage disease IXa1	2021-07-03	criteria provided, single submitter	clinical testing	A hemizygous missense variation in exon 33 of the PHKA2 gene that results in the amino acid substitution of Leucine for Proline at codon 1205 was detected. The observed variant c.3614C>T (p.Pro1205Leu) has not been reported in the 1000 genomes and gnomAD databases. The observed variant has previously been reported in multiple unrelated patients affected with glycogen storage disorders (Davit-Spraul et al 2011). The in silico prediction of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.
Revvity Omics, Revvity	RCV000011277	SCV002018779	pathogenic	Glycogen storage disease IXa1	2020-04-03	criteria provided, single submitter	clinical testing
OMIM	RCV000011277	SCV000031505	pathogenic	Glycogen storage disease IXa1	1995-02-01	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001091309	SCV001928255	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001091309	SCV001954283	pathogenic	not provided		no assertion criteria provided	clinical testing