ClinVar Miner

Submissions for variant NM_000155.4(GALT):c.974C>T (p.Pro325Leu) (rs111033794)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000022250 SCV000755884 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 325 of the GALT protein (p.Pro325Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs111033794, ExAC 0.009%). This variant has been observed on the opposite chromosome (in trans) from other pathogenic GALT variants in individuals affected with galactosemia (PMID: 9222760, 10573007). In addition, it has been reported as homozygous or in combination with other GALT variants in individuals affected with galactosemia (PMID: 10573007, 22944367, 20213376). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 25305). Experimental studies have shown that this missense change impairs GALT enzyme activity in vitro (PMID: 10573007). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000022250 SCV000798721 likely pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2018-03-22 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV001091819 SCV001248042 pathogenic not provided 2018-04-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000022250 SCV001363671 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2019-08-05 criteria provided, single submitter clinical testing Variant summary: GALT c.974C>T (p.Pro325Leu) results in a non-conservative amino acid change located in the C-terminal domain (IPR005850) of 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 1.2e-05 in 251618 control chromosomes (gnomAD). c.974C>T has been reported in the literature in multiple individuals (in homozygous and compound heterozygous state) affected with Galactosemia (e.g. Greber-Platzer_1997, Hirokawa_1999, Milankovics_2010). These data indicate that the variant is very likely to be associated with disease. At least one publication (Hirokawa_1999) reports experimental evidence using a cell line evaluating an impact on protein function and demonstrated reduced GALT activity (11% compared to WT controls). Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic (1x) or likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
Research and Development, ARUP Laboratories RCV000022250 SCV000042934 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2012-12-04 no assertion criteria provided clinical testing Converted during submission to Pathogenic.

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