ClinVar Miner

Submissions for variant NM_000155.4(GALT):c.793C>G (p.Pro265Ala) (rs111033764)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000595522 SCV000700294 uncertain significance not provided 2016-10-04 criteria provided, single submitter clinical testing
Invitae RCV000022206 SCV000825910 uncertain significance Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2018-03-01 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 265 of the GALT protein (p.Pro265Ala). The proline residue is weakly conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs111033764, ExAC 0.001%). This variant has been reported in combination with p.Arg204* in three individuals affected with galactosemia, being proven to be in cis in one of them (PMID: 17041746, 19224951). ClinVar contains an entry for this variant (Variation ID: 25265). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV001255517 SCV001431955 uncertain significance not specified 2020-08-20 criteria provided, single submitter clinical testing Variant summary: GALT c.793C>G (p.Pro265Ala) results in a non-conservative amino acid change located in the C-terminal domain (IPR005850) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250752 control chromosomes (gnomAD). c.793C>G has been reported in the literature in individuals affected with Galactosemia (Gort_2006, Carney_2009, Demirbas_2019), however, in at least one of these patients the variant was found in cis with a pathogenic variant (Gort_2006). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Research and Development, ARUP Laboratories RCV000022206 SCV000042888 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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