Submissions for variant NM_000155.4(GALT):c.200G>A (p.Arg67His)

gnomAD frequency: 0.00003  dbSNP: rs758430398

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000634556	SCV000755885	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2023-09-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 67 of the GALT protein (p.Arg67His). This variant is present in population databases (rs758430398, gnomAD 0.008%). This missense change has been observed in individual(s) with galactosemia (PMID: 22944367). ClinVar contains an entry for this variant (Variation ID: 203733). 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. This variant disrupts the p.Arg67 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8598637, 11152465, 22944367). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000634556	SCV000795523	uncertain significance	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2017-11-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235110	SCV003934325	uncertain significance	not specified	2023-05-18	criteria provided, single submitter	clinical testing	Variant summary: GALT c.200G>A (p.Arg67His) results in a non-conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, N-terminal (IPR005849) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251342 control chromosomes. c.200G>A has been reported in the literature in individuals affected with Galactosemia (Boutron_2012) and a pediatric patient with cataract (Patel_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22944367, 27878435). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One laboratory classified the variant as pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics	RCV000634556	SCV004198535	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2024-03-12	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000634556	SCV004804682	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2024-03-17	criteria provided, single submitter	research
Mayo Clinic Laboratories, Mayo Clinic	RCV004791313	SCV005413867	likely pathogenic	not provided	2024-08-05	criteria provided, single submitter	clinical testing	PP3_moderate, PM2, PM3, PM5
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV000634556	SCV003927816	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2023-04-01	no assertion criteria provided	clinical testing