Submissions for variant NM_000153.4(GALC):c.1949T>C (p.Leu650Pro)

gnomAD frequency: 0.00001  dbSNP: rs1249991480

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000671889	SCV000796920	uncertain significance	Galactosylceramide beta-galactosidase deficiency	2018-01-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000995226	SCV001149289	uncertain significance	not provided	2016-06-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001420862	SCV001623279	uncertain significance	not specified	2021-05-15	criteria provided, single submitter	clinical testing	Variant summary: GALC c.1949T>C (p.Leu650Pro) (legacy name p.Leu634Pro) 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 4e-06 in 247910 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1949T>C has always been reported in the literature as a complex allele in combination with another variant, p.Ile562Thr (legacy name p.Ile546Thr) in settings of newborn screening for Krabbe's disease and in compound heterozygosity with another complex allele combination in at-least one individual affected with Krabbe Disease (example, Saavendra-Matiz_2016, Bascou_2018). These report(s) do not provide unequivocal conclusions about association of the variant in isolation with Krabbe Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV000995226	SCV003816292	uncertain significance	not provided	2023-08-10	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000995226	SCV004026184	uncertain significance	not provided	2022-11-02	criteria provided, single submitter	clinical testing	PP3, PM2_SUP
Institute of Human Genetics, University of Leipzig Medical Center	RCV000671889	SCV004027692	likely pathogenic	Galactosylceramide beta-galactosidase deficiency	2023-06-06	criteria provided, single submitter	clinical testing	Criteria applied: PS3_MOD,PM3,PM2_SUP,PP3
Labcorp Genetics (formerly Invitae), Labcorp	RCV000671889	SCV004297146	uncertain significance	Galactosylceramide beta-galactosidase deficiency	2023-08-24	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 555965). 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. Experimental studies have shown that this missense change affects GALC function (PMID: 27638593). 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. This variant is also known as p.L634P. This missense change has been observed in individual(s) with Krabbe disease (PMID: 30089515). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 650 of the GALC protein (p.Leu650Pro).
Institute of Human Genetics, University Hospital Muenster	RCV003985407	SCV004801719	likely pathogenic	See cases	2023-05-24	criteria provided, single submitter	clinical testing	ACMG categories: PM2,PM3,PP3,PP4
Natera, Inc.	RCV000671889	SCV002091306	uncertain significance	Galactosylceramide beta-galactosidase deficiency	2020-12-29	no assertion criteria provided	clinical testing