ClinVar Miner

Submissions for variant NM_000155.4(GALT):c.1132A>G (p.Ile378Val)

gnomAD frequency: 0.00014  dbSNP: rs111033819
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507865 SCV000603800 uncertain significance not specified 2017-02-16 criteria provided, single submitter clinical testing
Invitae RCV000022280 SCV000965232 uncertain significance Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2022-10-25 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 378 of the GALT protein (p.Ile378Val). This variant is present in population databases (rs111033819, gnomAD 0.02%). This missense change has been observed in individual(s) with galactosemia (PMID: 11678552). ClinVar contains an entry for this variant (Variation ID: 25334). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Illumina Laboratory Services, Illumina RCV000022280 SCV001331420 uncertain significance Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Myriad Genetics, Inc. RCV000022280 SCV002060300 uncertain significance Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2021-11-08 criteria provided, single submitter clinical testing NM_000155.3(GALT):c.1132A>G(I378V) is a missense variant classified as a variant of uncertain significance in the context of galactosemia. I378V has been observed in cases with relevant disease (PMID: 11678552). Functional assessments of this variant are not available in the literature. I378V has been observed in population frequency databases (gnomAD: NFE 0.02%). In summary, there is insufficient evidence to classify NM_000155.3(GALT):c.1132A>G(I378V) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000507865 SCV002556190 uncertain significance not specified 2022-06-27 criteria provided, single submitter clinical testing Variant summary: GALT c.1132A>G (p.Ile378Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 282716 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in GALT causing Galactosemia (0.00011 vs 0.0029), allowing no conclusion about variant significance. c.1132A>G has been reported in the literature in at least one individual affected with Galactosemia (Zekanowski_2001). However, this report does not provide unequivocal conclusions about association of the variant with Galactosemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: all classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics RCV000022280 SCV002780731 uncertain significance Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2022-04-18 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001354665 SCV001549335 uncertain significance not provided no assertion criteria provided clinical testing The GALT p.Ile269Val variant was identified in 1 of 154 proband chromosomes (frequency: 0.0065) from patients with galactosaemia (Zekanowski_2001_PMID:11678552). The variant was identified in dbSNP (ID: rs111033819) and ClinVar (classified as uncertain significance by ARUP Laboratories, Counsyl and Invitae, and as pathogenic by Research and Development, ARUP Laboratories). The variant was identified in control databases in 31 of 282716 chromosomes at a frequency of 0.0001097 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 27 of 129094 chromosomes (freq: 0.000209), European (Finnish) in 3 of 25098 chromosomes (freq: 0.00012) and Ashkenazi Jewish in 1 of 10360 chromosomes (freq: 0.000097), but was not observed in the African, Latino, East Asian, Other or South Asian populations. The p.Ile269 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Natera, Inc. RCV001826504 SCV002085261 uncertain significance Galactosemia 2018-04-20 no assertion criteria provided clinical testing

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