Submissions for variant NM_000153.4(GALC):c.560A>T (p.Asp187Val)

dbSNP: rs997021099

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000796371	SCV000935881	pathogenic	Galactosylceramide beta-galactosidase deficiency	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 187 of the GALC protein (p.Asp187Val). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with Krabbe disease (PMID: 8687180, 20886637, 27442402). 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 Asp171Val. ClinVar contains an entry for this variant (Variation ID: 642832). 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 GALC protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GALC function (PMID: 27638593). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000796371	SCV002041494	likely pathogenic	Galactosylceramide beta-galactosidase deficiency	2022-08-08	criteria provided, single submitter	clinical testing	Variant summary: GALC c.560A>T (p.Asp187Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249464 control chromosomes (gnomAD). The variant c.560A>T (aka c.512A>T; p.Asp171Val), has been reported in the literature in multiple compound heterozygous individuals affected with Krabbe Disease (e.g. Luzi_1996, Tappino_2010, Fiumara_2011, Gucev_2015, Dimitriou_2016), and all of these cases were reported to have a significantly reduced GALC enzyme activity. These data indicate that the variant is likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant in isolation resulted in about 5-10% residual activity compared to the normal (Saavedra-Matiz_2016), however, when the variant was expressed in cis, together with the frequent polymorphisms I546T (aka Ile562Thr) and R168C (aka Arg184Cys) as a haplotype, it resulted almost undetectable GALC enzyme activity (Luzi_1996, Saavedra-Matiz_2016); authors of the later study noted that the I546T polymorphism is known to reduce the measured GALC activity partially (Saavedra-Matiz_2016). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both of them classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Revvity Omics, Revvity	RCV003144601	SCV003832495	likely pathogenic	not provided	2022-05-10	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000796371	SCV001454073	likely pathogenic	Galactosylceramide beta-galactosidase deficiency	2020-09-16	no assertion criteria provided	clinical testing
GeneReviews	RCV000796371	SCV004035015	not provided	Galactosylceramide beta-galactosidase deficiency		no assertion provided	literature only