ClinVar Miner

Submissions for variant NM_000154.2(GALK1):c.593C>T (p.Ala198Val) (rs80084721)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000005987 SCV000631404 uncertain significance Deficiency of galactokinase 2019-11-12 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 198 of the GALK1 protein (p.Ala198Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs80084721, ExAC 1.5%). This variant, also known as the 'Osaka' variant, is reported at a relatively high frequency in the Japanese (4.1%) and Korean (2.8%) populations; individuals from these populations who are homozygous for this variant have been observed to have reduced galactokinase activity (~20% of normal) and mild galactokinase deficiency (PMID: 11231902). In addition, this variant is found at a higher frequency (7.8%) in Japanese adults with bilateral cataracts than in general Japanese population (4.1%) (PMID: 11231902). This data suggests that the Osaka variant may be associated with an increased risk for bilateral cataracts, although larger population studies are needed to confirm this association. ClinVar contains an entry for this variant (Variation ID: 5633). Experimental studies have demonstrated that this missense change does not significantly affect the enzymatic activity of the GALK1 protein (PMID: 12694189, 11231902). However, expression analysis in crude blood extracts from individuals who are homozygous for this variant indicate that this variant results in an 80% reduction in expression of the GALK1 protein (PMID: 11231902). In summary, this variant is a rare missense change that has been shown to result in a partial loss of GALK1 protein expression and enzymatic activity in vivo. While this variant does not appear to cause classic galactokinase deficiency, it may confer an increased risk for bilateral cataracts in adults. However, larger population studies are needed to demonstrate this conclusively. Therefore, this missense change has been classified as a Variant of Uncertain Significance.
Counsyl RCV000005987 SCV000800800 likely benign Deficiency of galactokinase 2017-12-20 criteria provided, single submitter clinical testing
Mendelics RCV000005987 SCV001140835 uncertain significance Deficiency of galactokinase 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000005987 SCV001285771 uncertain significance Deficiency of galactokinase 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
OMIM RCV000005987 SCV000026169 pathogenic Deficiency of galactokinase 2001-04-01 no assertion criteria provided literature only
Natera, Inc. RCV000005987 SCV001459342 uncertain significance Deficiency of galactokinase 2020-01-07 no assertion criteria provided clinical testing

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