ClinVar Miner

Submissions for variant NM_000155.4(GALT):c.197C>T (p.Pro66Leu) (rs111033656)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000022066 SCV000788547 uncertain significance Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2017-12-28 criteria provided, single submitter clinical testing
Invitae RCV000022066 SCV000952788 uncertain significance Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2018-11-26 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 66 of the GALT protein (p.Pro66Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs111033656, ExAC 0.01%). This variant has been observed in an individual with a positive newborn screening result (PMID: 25087612). ClinVar contains an entry for this variant (Variation ID: 25136). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 RCV001194273 SCV001363668 uncertain significance not specified 2019-02-15 criteria provided, single submitter clinical testing Variant summary: GALT c.197C>T (p.Pro66Leu) results in a non-conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, N-terminal domain 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 4e-05 in 277122 control chromosomes. This frequency is not higher than expected for a pathogenic variant in GALT causing Galactosemia (4e-05 vs 0.0029), allowing no conclusion about variant significance. A publication reports a compound heterozygote patient (Shin 2004), who carried the variant c.197C>A that would cause a missense change of Pro66His however, in the report a missense change of Pro66Leu is indicated. Authors do not provide sequence data therefore it remains unclear whether it is the variant of interest that was reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. However, another well-established clinical diagnostic laboratory, ARUP, has classified the variant as pathogenic prior to 2014. Furthermore, another variant, c.197C>A, affecting the same nucleotide but causing a different missense change, Pro66His has been reported in ClinVar, along with additional variants affecting nearby residues, p.R67C, p.R67H, p.H68P, suggesting the region is important for GALT function. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Research and Development, ARUP Laboratories RCV000022066 SCV000042741 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2012-12-04 no assertion criteria provided clinical testing Converted during submission to Pathogenic.
Seelig Lab,University of Washington RCV000767307 SCV000897871 not provided not provided no assertion provided in vitro

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