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

gnomAD frequency: 0.00124  dbSNP: rs80084721

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000005987	SCV000631404	uncertain significance	Deficiency of galactokinase	2022-09-07	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 198 of the GALK1 protein (p.Ala198Val). This variant is present in population databases (rs80084721, gnomAD 1.5%). This missense change has been observed in individual(s) with mild galactokinase deficiency and/or bilateral cataracts (PMID: 11231902). It has also been observed to segregate with disease in related individuals. This variant is also known as Osaka variant. ClinVar contains an entry for this variant (Variation ID: 5633). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects GALK1 function (PMID: 11231902, 12694189). 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.
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 Laboratory Services, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824561	SCV002074533	likely benign	not specified	2022-01-05	criteria provided, single submitter	clinical testing	Variant summary: GALK1 c.593C>T (p.Ala198Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 250192 control chromosomes, predominantly at a frequency of 0.015 within the East Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 13-fold of the estimated maximal expected allele frequency (MPAF) for a pathogenic variant in GALK1 causing Deficiency of Galactokinase phenotype (0.0011). However, the variant was reported in certain East Asian subpopulations with an even higher allele frequency, e.g. in the Japanese, with an allele frequency of 0.044-0.047 (in the HGVD-Kyoto and jMorp databases). This frequency is about 40-fold higher than the of the MPAF (0.0011), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.593C>T (aka. Osaka variant), was found in 4 compound heterozygous Japanese newborns with decreased GALK activity, and all of them carried a (presumed) null variant in trans, however, none of these cases had cataract or other clinical manifestations during the neonatal period (Okano_2001). The authors of this study also performed a population analysis, which revealed that the prevalence of A198V is 4.1% in Japanese and 2.8% in Koreans, with a lower incidence in Taiwanese and Chinese, and no incidence in blacks or whites from the United States. On the other hand, authors found that the variant had a significantly higher frequency (7.8%) in Japanese adults (>55 years of age) with bilateral cataract, therefore the Osaka variant might be one of the genetic risk factors in age-related cataract formation (Okano_2001). To our knowledge, the variant has not been reported in the literature in individuals affected with congenital, neonatal, or early childhood bilateral cataracts that seems to be the only consistent manifestation in patients with classic GALK1 deficiency (Rubio-Gozalbo_2021). Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that while the variant protein had normal Km, the in vivo activity in patient derived samples was about 20% of the normal, which corresponded to the decreased amount and activity for the variant protein expressed in mammalian cells, suggesting a decreased stability for the variant protein (Okano_2001). However, the variant protein was found to have a normal expression and activity (Vmax and Km) in a bacterial expression system (Timson_2003). These data suggest that the variant may result in an increased degradation in human (mammalian) cells (Timson_2003). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as VUS (n=4) or likely benign (n=1). Based on the evidence outlined above, the although the variant might represent a risk-factor for age-related cataract formation, it is unlikely to be associated with congenital cataracts, therefore the variant was classified as likely benign.
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