Submissions for variant NM_001008216.2(GALE):c.658C>T (p.Arg220Trp)

gnomAD frequency: 0.00001  dbSNP: rs764909409

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000727555	SCV000854785	uncertain significance	not provided	2018-07-13	criteria provided, single submitter	clinical testing
Invitae	RCV001337968	SCV001531596	uncertain significance	UDPglucose-4-epimerase deficiency	2022-06-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 220 of the GALE protein (p.Arg220Trp). This variant is present in population databases (rs764909409, gnomAD 0.005%). This missense change has been observed in individual(s) with epimerase deficiency galactosemia (PMID: 23430501). ClinVar contains an entry for this variant (Variation ID: 592180). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx	RCV000727555	SCV001986374	uncertain significance	not provided	2021-02-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23644136, 23430501)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323702	SCV004028682	uncertain significance	not specified	2023-07-10	criteria provided, single submitter	clinical testing	Variant summary: GALE c.658C>T (p.Arg220Trp) results in a non-conservative amino acid change located in the NAD(P)-binding domain (IPR 016040) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 249592 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.658C>T has been reported in the literature in the presumed homozygous state (father not available for confirmatory testing) in a pair of monozygotic twins who were suspected of UDPglucose-4-Epimerase Deficiency based on elevation of total galactose during initial newborn screening and variable GALE enzyme activity, jaundice and failure to thrive in early follow-up; however, both children had multiple concurrent abnormalities, including severe vitamin D-deficiency rickets and Williams syndrome, and by 18 months they tolerated normal diets (Liu_2013). Therefore, this report does not provide unequivocal conclusions about association of the variant with UDPglucose-4-Epimerase Deficiency. Functional experiments in patient lymphoblasts and in yeast expressing the variant found a marginally lowered GALE activity, with the most pronounced variant effect resulting in >50% of normal activity (Liu_2013). The following publication has been ascertained in the context of this evaluation (PMID: 23430501). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.