Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
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, |
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, |
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, |
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, |
RCV000800933 | SCV001463624 | pathogenic | Deficiency of galactokinase | 2020-09-16 | no assertion criteria provided | clinical testing |