Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000522459 | SCV000618462 | pathogenic | not provided | 2017-11-01 | criteria provided, single submitter | clinical testing | The P89L variant in the GALC gene has been reported previously in several infants with low GALC activity on newborn screening, including at least one individual who was found to have a partial gene deletion on the oppositive GALC allele (in trans) (Orsini et al., 2016). The P89L variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The P89L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Functional studies demonstrate that the P89L variant is associated with decreased enzyme activity (Saavedra-Matiz et al., 2016). We interpret P89L as a pathogenic variant. |
Invitae | RCV000673406 | SCV000822850 | uncertain significance | Galactosylceramide beta-galactosidase deficiency | 2022-09-07 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 89 of the GALC protein (p.Pro89Leu). This variant is present in population databases (rs201422931, gnomAD 0.03%). This missense change has been observed in individual(s) with low GALC enzyme activity (PMID: 26795590). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.P73L. ClinVar contains an entry for this variant (Variation ID: 449966). 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"). Experimental studies have shown that this missense change affects GALC function (PMID: 27638593). 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. |
Eurofins Ntd Llc |
RCV000522459 | SCV000857362 | uncertain significance | not provided | 2017-10-05 | criteria provided, single submitter | clinical testing | |
Illumina Laboratory Services, |
RCV000673406 | SCV001273753 | uncertain significance | Galactosylceramide beta-galactosidase deficiency | 2018-01-12 | criteria provided, single submitter | clinical testing | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. |
Mayo Clinic Laboratories, |
RCV000522459 | SCV001714493 | uncertain significance | not provided | 2023-06-21 | criteria provided, single submitter | clinical testing | PP3, PM2, PM3_supporting |
Laboratorio de Genetica e Diagnostico Molecular, |
RCV002252151 | SCV002523276 | uncertain significance | See cases | 2019-03-18 | criteria provided, single submitter | clinical testing | ACMG classification criteria: PM1, PM2, PP3 |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV002307527 | SCV002600293 | uncertain significance | not specified | 2022-10-05 | criteria provided, single submitter | clinical testing | Variant summary: GALC c.266C>T (p.Pro89Leu) 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 0.00014 in 249270 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GALC causing Krabbe Disease (0.00014 vs 0.0022), allowing no conclusion about variant significance. c.266C>T has been reported in the literature in an infant with low GALC enzyme activity during newborn screening who carried a large deletion on the second allele (Orsini_2016). These data do not allow any conclusion about variant significance. The variant was reported to lead to around 20% residual GALC activity in a in vitro study (Saavedra-Martin_2016). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Six submitters classified the variant as VUS while one classified as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
Revvity Omics, |
RCV000522459 | SCV003816290 | uncertain significance | not provided | 2019-11-01 | criteria provided, single submitter | clinical testing | |
Ce |
RCV000522459 | SCV004041912 | uncertain significance | not provided | 2023-09-01 | criteria provided, single submitter | clinical testing | GALC: PM2, PP3, PS3:Supporting |
Counsyl | RCV000673406 | SCV000798605 | uncertain significance | Galactosylceramide beta-galactosidase deficiency | 2018-03-14 | no assertion criteria provided | clinical testing |