ClinVar Miner

Submissions for variant NM_000153.4(GALC):c.195G>C (p.Gly65=) (rs886042057)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000513714 SCV000330946 likely pathogenic not provided 2017-05-18 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000513714 SCV000610708 pathogenic not provided 2017-09-06 criteria provided, single submitter clinical testing
Counsyl RCV000400667 SCV000799504 likely pathogenic Galactosylceramide beta-galactosidase deficiency 2018-04-26 criteria provided, single submitter clinical testing
Invitae RCV000400667 SCV000964060 likely pathogenic Galactosylceramide beta-galactosidase deficiency 2020-07-21 criteria provided, single submitter clinical testing This sequence change affects codon 65 of the GALC mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GALC protein. This variant also falls at the last nucleotide of exon 1 of the GALC coding sequence, which is part of the consensus splice site for this exon. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been observed in individuals affected with late-onset globoid-cell leukodystrophy (PMID: 8940268, 9005874, 23197103, Invitae). This variant is also known as c.147G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 280959). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this silent change results in aberrant splicing of the GALC primary transcript (PMID: 8940268). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000400667 SCV001443768 pathogenic Galactosylceramide beta-galactosidase deficiency 2020-03-13 criteria provided, single submitter clinical testing This variant affects the splice donor site of exon 1 and is therefore predicted to interfere with splicing and result in loss of normal protein function. This variant has been previously reported in individuals with late onset Krabbe's disease as a compound heterozygous change in two related individuals (PMID: 9005874, 8940268), the compound homozygous state in one individual (PMID: 23197103), and in one individual with no second variant identified (PMID: 23197103). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.006% (2/31320) and thus is presumed to be rare. Multiple splice prediction tools suggest this variant is likely to interfere with normal splicing. This variant is present in the ClinVar database (Variation ID: 280959). Functional studies support a damaging effect of this variant on splicing (PMID: 8940268). . Based on the available evidence, the c.195G>C (p.Gly65=) variant is classified as Pathogenic.

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