Submissions for variant NM_000153.4(GALC):c.830G>A (p.Ser277Asn)

dbSNP: rs1886145312

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences	RCV001250794	SCV001244262	likely pathogenic	Galactosylceramide beta-galactosidase deficiency	2019-07-05	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001250794	SCV005040029	pathogenic	Galactosylceramide beta-galactosidase deficiency	2024-03-08	criteria provided, single submitter	clinical testing	Variant summary: GALC c.830G>A (p.Ser277Asn) results in a conservative amino acid change located in the Glycosyl hydrolase family 59, catalytic domain (IPR049161) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249284 control chromosomes. c.830G>A has been reported in the literature as a homozygous genotype in multiple individuals affected with features of Krabbe Disease/Leukodystrophies (example, Mahdieh_2021, Ashrafi_2023). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 37597066, 33547378). ClinVar contains an entry for this variant (Variation ID: 873006). Based on the evidence outlined above, the variant was classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004545052	SCV005040804	pathogenic	Fabry disease	2024-03-08	criteria provided, single submitter	clinical testing	Variant summary: GLA c.830G>A (p.Trp277X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 183402 control chromosomes (gnomAD). c.830G>A has been reported in the literature in multiple individuals affected with Classic Fabry Disease (Topaloglu_1999, Nakano_2015, Sivley_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence,	RCV001250794	SCV001250613	uncertain significance	Galactosylceramide beta-galactosidase deficiency		no assertion criteria provided	clinical testing