ClinVar Miner

Submissions for variant NM_000153.4(GALC):c.908C>T (p.Ser303Phe)

gnomAD frequency: 0.00001  dbSNP: rs756352952
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000522818 SCV000330944 pathogenic not provided 2015-09-29 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000285229 SCV000389254 pathogenic Galactosylceramide beta-galactosidase deficiency 2018-05-03 criteria provided, single submitter clinical testing The GALC c.908C>T (p.Ser303Phe) missense variant, also referred to as p.Ser287Phe, has been reported in at least four studies in which it is found in a total of five unrelated individuals, all affected with an infantile form of galactosylceramide beta-galactosidase deficiency disease (Krabbe disease), including in one in a homozygous state and four in a compound heterozygous state (Wenger et al. 1997; Selleri et al. 2000; Tappino et al. 2010; Zhao et al. 2017). GALC activity in patient leukocytes or fibroblasts ranged from 3 - 15% compared to control levels. All of the compound heterozygotes carried missense variants on the second allele, with one found in trans with a complex allele of two missense variants. Control data are unavailable for this variant, which is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. The serine residue is partially conserved. Expression of the variant in COS-1 cells revealed no GALC activity in vitro (Jardim et al. 1999). Based on the evidence, the p.Ser303Phe variant is classified as pathogenic for Krabbe disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx RCV000522818 SCV000617679 pathogenic not provided 2023-08-07 criteria provided, single submitter clinical testing Expression studies on COS-1 cells showed a dramatic reduction of GALC activity of the mutated expressed protein (Jardim et al., 1999); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9338580, 20886637, 28598007, 33176815, 30089515, 11151421, 10448809)
Counsyl RCV000285229 SCV000800751 likely pathogenic Galactosylceramide beta-galactosidase deficiency 2017-03-29 criteria provided, single submitter clinical testing
Invitae RCV000285229 SCV001224311 pathogenic Galactosylceramide beta-galactosidase deficiency 2023-12-18 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 303 of the GALC protein (p.Ser303Phe). This variant is present in population databases (rs756352952, gnomAD 0.004%). This missense change has been observed in individual(s) with Krabbe disease (PMID: 9338580, 11151421, 20886637, 30089515). This variant is also known as Ser287Phe. ClinVar contains an entry for this variant (Variation ID: 280957). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GALC function (PMID: 10448809). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV000522818 SCV001249967 pathogenic not provided 2017-01-01 criteria provided, single submitter clinical testing
Revvity Omics, Revvity Omics RCV000522818 SCV002021213 pathogenic not provided 2020-03-04 criteria provided, single submitter clinical testing
3billion RCV000285229 SCV002318482 pathogenic Galactosylceramide beta-galactosidase deficiency 2022-03-22 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000280957, PMID:9338580). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 10448809). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.957>=0.6, 3CNET: 0.946>=0.75). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0000284). The variant is in trans with NM_000153.4:c.136G>T variant (3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics RCV000285229 SCV002801173 likely pathogenic Galactosylceramide beta-galactosidase deficiency 2022-05-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000285229 SCV003922542 pathogenic Galactosylceramide beta-galactosidase deficiency 2023-03-22 criteria provided, single submitter clinical testing Variant summary: GALC c.908C>T (p.Ser303Phe) 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. Two computational tools predict a significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.4e-05 in 245686 control chromosomes (gnomAD). c.908C>T has been reported in the literature as a biallelic genotype in multiple individuals affected with Krabbe Disease, primarily with infantile onset (e.g. Wenger_1997, Selleri_2000, Tappino_2010, Zhao_2018, Krieg_2020). These data indicate that the variant is very likely to be associated with disease. Ten submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=8)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine RCV000285229 SCV004047462 pathogenic Galactosylceramide beta-galactosidase deficiency criteria provided, single submitter clinical testing The missense variant c.908C>T (p.Ser303Phe) in GALC gene has been reported in heterozygous state in several individuals affected with Krabbe disease (Bascou N et al.). The S303F was also reported in a patient with infantile-onset Krabbe disease who was homozygous for S303F (Wenger et al.). Experimental studies have shown that predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies (Jardim et al.). This variant has allele frequency 0.002% in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic. The S303F variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The amino acid change p.Ser303Phe in GALC is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Natera, Inc. RCV000285229 SCV002093643 pathogenic Galactosylceramide beta-galactosidase deficiency 2021-06-03 no assertion criteria provided clinical testing

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