Submissions for variant NM_000155.4(GALT):c.199C>T (p.Arg67Cys)

gnomAD frequency: 0.00001  dbSNP: rs111033658

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723719	SCV000110053	pathogenic	not provided	2013-07-30	criteria provided, single submitter	clinical testing
Invitae	RCV000022067	SCV000631389	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2023-08-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GALT function (PMID: 11152465). 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. ClinVar contains an entry for this variant (Variation ID: 25137). This missense change has been observed in individual(s) with galactosemia (PMID: 8598637, 22944367). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs111033658, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 67 of the GALT protein (p.Arg67Cys).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000022067	SCV000917422	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2018-05-07	criteria provided, single submitter	clinical testing	Variant summary: GALT c.199C>T (p.Arg67Cys) results in a non-conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, N-terminal (IPR005849) 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 3.2e-05 in 30924 control chromosomes (gnomAD). c.199C>T has been reported in the literature in individuals affected with Galactosemia (Sommer 1995, Boutron 2012). These data indicate that the variant may be associated with disease. Two publications reported experimental evidence evaluating an impact on protein function (Sommer 1995, Riehman 2001). The most pronounced variant effect resulted in <10% of normal activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000723719	SCV002512870	pathogenic	not provided	2022-04-29	criteria provided, single submitter	clinical testing	Published functional studies demonstrate 2% residual enzyme activity compared to wild-type (Riehman et al., 2001); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27005423, 11152465, 20008339, 10384398, 15633893, 8598637, 22944367)
Baylor Genetics	RCV000022067	SCV004198528	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2023-07-12	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001831595	SCV002085183	pathogenic	Galactosemia	2017-08-29	no assertion criteria provided	clinical testing