Submissions for variant NM_000155.4(GALT):c.1132A>G (p.Ile378Val) (rs111033819)

Total submissions: 6

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
Counsyl	RCV000022280	SCV000800504	uncertain significance	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2017-03-06	criteria provided, single submitter	clinical testing
Invitae	RCV000022280	SCV000965232	uncertain significance	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2018-09-24	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with valine at codon 378 of the GALT protein (p.Ile378Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs111033819, ExAC 0.02%). This variant has been observed in an individual affected 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, suggesting that this missense change does not adversely affect protein function. 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.
Illumina Clinical Services Laboratory,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.
Research and Development, ARUP Laboratories	RCV000022280	SCV000042965	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2012-12-04	no assertion criteria provided	clinical testing	Converted during submission to Pathogenic.
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.