ClinVar Miner

Submissions for variant NM_000153.4(GALC):c.908C>T (p.Ser303Phe) (rs756352952)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000522818 SCV000330944 pathogenic not provided 2015-09-29 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 2018-08-30 criteria provided, single submitter clinical testing The S303F variant has been reported previously, using alternate nomenclature, in patients with Krabbe disease who also harbored a pathogenic or likely pathogenic variant in the GALC gene (Selleri et al. 2000; Tappino et al. 2010). S303F was also reported in a patient with infantile-onset Krabbe disease who was homozygous for S303F (Wenger et al. 1997). 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret this variant as a pathogenic variant.
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 2020-10-15 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 303 of the GALC protein (p.Ser303Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs756352952, ExAC 0.009%). This variant has been observed in several individuals affected with Krabbe disease (PMID: 9338580, 30089515, 11151421, 20886637). This variant is also known as Ser287Phe in the literature. ClinVar contains an entry for this variant (Variation ID: 280957). This variant has been reported to affect GALC protein function (PMID: 10448809). Algorithms developed to 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. For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000522818 SCV001249967 pathogenic not provided 2017-01-01 criteria provided, single submitter clinical testing

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