Submissions for variant NM_000155.4(GALT):c.1018G>A (p.Glu340Lys)

gnomAD frequency: 0.00001  dbSNP: rs111033806

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000022263	SCV001377663	uncertain significance	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2022-10-21	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 340 of the GALT protein (p.Glu340Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GALT-related conditions (PMID: 10649501, 20213376, 22944367, 28065439). ClinVar contains an entry for this variant (Variation ID: 25317). 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. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001582494	SCV001821392	uncertain significance	not specified	2021-08-26	criteria provided, single submitter	clinical testing	Variant summary: GALT c.1018G>A (p.Glu340Lys) results in a conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, C-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251462 control chromosomes. c.1018G>A has been reported in the literature in individuals affected with Galactosemia in the homozygous and compound heterozygous state with the Duarte allele in cis (Kozak_2000, Milankovics_2010), the compound heterozygous without reporting the of presence of Duarte allele (Siripunthana_2013) and in the heterozygous state without a reported second allele and unknown Duarte allele status (Welling_2017). The penetrance of the variant in isolation is unknown. Additionally, to our knowledge, no experimental studies have been performed on this variant in isolation. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics	RCV000022263	SCV004198538	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2023-06-12	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001826503	SCV002085255	uncertain significance	Galactosemia	2021-08-10	no assertion criteria provided	clinical testing