Submissions for variant NM_000153.4(GALC):c.136G>T (p.Asp46Tyr)

gnomAD frequency: 0.00006  dbSNP: rs751975987

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781395	SCV000919391	pathogenic	Galactosylceramide beta-galactosidase deficiency	2017-12-04	criteria provided, single submitter	clinical testing	Variant summary: The GALC c.136G>T (p.Asp46Tyr) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 9/149232 control chromosomes at a frequency of 0.0000603, which does not exceed the estimated maximal expected allele frequency of a pathogenic GALC variant (0.0022361). The variant was reported in several patients in compound heterozygosity with at least two likely pathogenic/pathogenic mutations and biochemical findings suggestive of Krabbe disease (Pchelina_2014; Zhao_2017). Per latest published reports, c.136G>T is associated with a mild clinical course of disease (Zhao_2017). Taken together, this variant is classified as Pathogenic.
Invitae	RCV000781395	SCV000946629	pathogenic	Galactosylceramide beta-galactosidase deficiency	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 46 of the GALC protein (p.Asp46Tyr). This variant is present in population databases (rs751975987, gnomAD 0.06%). This missense change has been observed in individual(s) with Krabbe disease (PMID: 24078576, 28598007, 31185936; externalcommunication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 633229). 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%. For these reasons, this variant has been classified as Pathogenic.
3billion	RCV000781395	SCV002058894	pathogenic	Galactosylceramide beta-galactosidase deficiency	2022-01-03	criteria provided, single submitter	clinical testing	The variant was co-segregated with Krabbe disease in multiple affected family members (PMID: 31185936, PP1_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.841, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000059, PM2_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000633229, PMID:24078576, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 25265039, 28598007, PM3_S). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Natera, Inc.	RCV000781395	SCV002093663	pathogenic	Galactosylceramide beta-galactosidase deficiency	2020-12-03	no assertion criteria provided	clinical testing