ClinVar Miner

Submissions for variant NM_000155.4(GALT):c.775C>T (p.Arg259Trp)

gnomAD frequency: 0.00001  dbSNP: rs786204763
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000723394 SCV000232473 pathogenic not provided 2015-06-08 criteria provided, single submitter clinical testing
Baylor Genetics RCV000169625 SCV001163244 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2024-03-27 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000169625 SCV001579739 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2023-10-20 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 259 of the GALT protein (p.Arg259Trp). This variant is present in population databases (rs786204763, gnomAD 0.003%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with galactose-1-phosphate uridyltransferase deficiency (PMID: 8741038, 22944367, 23749220, 25268296). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 189191). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GALT protein function. Experimental studies have shown that this missense change affects GALT function (PMID: 11152465). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg259 amino acid residue in GALT. Other variant(s) that disrupt this residue have been observed in individuals with GALT-related conditions (PMID: 22461411), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000723394 SCV001771445 pathogenic not provided 2023-07-12 criteria provided, single submitter clinical testing Functional analysis found this variant is associated with significantly reduced GALT enzyme activity (Riehman et al., 2001); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31194895, 11261429, 23749220, 20008339, 17041746, 31194252, 10408771, 31589614, 11152465, 8741038)
Myriad Genetics, Inc. RCV000169625 SCV002060215 likely pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2021-11-08 criteria provided, single submitter clinical testing NM_000155.3(GALT):c.775C>T(R259W) is a missense variant classified as likely pathogenic in the context of galactosemia. R259W has been observed in cases with relevant disease (PMID: 8892021, 10535394, 21779791, 22944367, 25268296, 27363831, 9396569, 31194895, 23749220). Functional assessments of this variant are available in the literature (PMID: 11152465). R259W has been observed in population frequency databases (gnomAD: AMR 0.003%). In summary, NM_000155.3(GALT):c.775C>T(R259W) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Fulgent Genetics, Fulgent Genetics RCV000169625 SCV002799427 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2022-05-25 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000723394 SCV005413881 pathogenic not provided 2024-01-09 criteria provided, single submitter clinical testing PP3, PP4, PM2_moderate, PM3_strong, PS3
Natera, Inc. RCV001831991 SCV002085235 pathogenic Galactosemia 2017-08-29 no assertion criteria provided clinical testing

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