Submissions for variant NM_000154.2(GALK1):c.766C>T (p.Arg256Trp)

gnomAD frequency: 0.00010  dbSNP: rs376790302

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000800933	SCV000940678	pathogenic	Deficiency of galactokinase	2024-01-09	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 256 of the GALK1 protein (p.Arg256Trp). This variant is present in population databases (rs376790302, gnomAD 0.09%). This missense change has been observed in individuals with clinical features of galactosemia (PMID: 10570908, 17517531, 28418495). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 646613). 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) performed at Invitae indicates that this missense variant is expected to disrupt GALK1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GALK1 function (PMID: 10570908, 17517531). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000800933	SCV002024147	pathogenic	Deficiency of galactokinase	2020-12-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000800933	SCV004197923	likely pathogenic	Deficiency of galactokinase	2024-03-16	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000800933	SCV004809946	likely pathogenic	Deficiency of galactokinase	2024-04-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000800933	SCV005380944	pathogenic	Deficiency of galactokinase	2024-08-16	criteria provided, single submitter	clinical testing	Variant summary: GALK1 c.766C>T (p.Arg256Trp) 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 allele was found at a frequency of 0.0002 in 250958 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GALK1 causing Deficiency Of Galactokinase (0.0002 vs 0.0011), allowing no conclusion about variant significance. c.766C>T has been reported in the literature in compound heterozygous or homozygous individuals affected with Deficiency Of Galactokinase (e.g. Asada_1999, Chen_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal enzyme activity in vitro (e.g. Asada_1999). The following publications have been ascertained in the context of this evaluation (PMID: 10570908, 28418495). ClinVar contains an entry for this variant (Variation ID: 646613). Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc.	RCV000800933	SCV001463624	pathogenic	Deficiency of galactokinase	2020-09-16	no assertion criteria provided	clinical testing