Submissions for variant NM_000155.4(GALT):c.512T>C (p.Phe171Ser)

gnomAD frequency: 0.00004  dbSNP: rs111033715

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723392	SCV000110063	pathogenic	not provided	2018-02-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000003800	SCV000631393	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 171 of the GALT protein (p.Phe171Ser). This variant is present in population databases (rs111033715, gnomAD 0.02%). This missense change has been observed in individual(s) with galactosemia (PMID: 1610789, 18956253, 22944367, 23022339, 27176039). ClinVar contains an entry for this variant (Variation ID: 3616). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GALT function (PMID: 1610789, 10811638, 23583749). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000003800	SCV000695694	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2016-09-22	criteria provided, single submitter	clinical testing	Variant summary: The GALT c.512T>C (p.Phe171Ser) variant is located in the Galactose-1-phosphate uridyl transferase, N-terminal domain causing a missense change involving a conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121466, which does not exceed the estimated maximal expected allele frequency for a pathogenic GALT variant of 1/346. Multiple publications cite the variant in affected individuals as homozygous or compound heterozygous, along with multiple clinical diagnostic laboratories citing the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000003800	SCV000885500	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2023-10-30	criteria provided, single submitter	clinical testing	The GALT c.512T>C; p.Phe171Ser variant (rs111033715) is described in several studies to have reduced or a complete loss of enzymatic activity (Crews 2000, McCorvie 2013, Reichardt 1992, Riehman 2001, Wang 1998). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 3616). It is found in the general African American population with a low allele frequency of 0.02% (5/24016 alleles) in the Genome Aggregation Database. The phenylalanine at codon 171 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.985). Based on available information, this variant is considered to be pathogenic. References: Crews C et al. Functional consequence of substitutions at residue 171 in human galactose-1-phosphate uridylyltransferase. J Biol Chem. 2000 Jul 28;275(30):22847-53. PMID: 10811638 McCorvie TJ et al. Misfolding of galactose 1-phosphate uridylyltransferase can result in type I galactosemia. Biochim Biophys Acta. 2013 Aug;1832(8):1279-93. PMID: 23583749 Reichardt JK et al. Molecular characterization of two galactosemia mutations and one polymorphism: implications for structure-function analysis of human galactose-1-phosphate uridyltransferase. Biochemistry. 1992 Jun 23;31(24):5430-3. PMID: 1610789 Riehman K et al. Relationship between genotype, activity, and galactose sensitivity in yeast expressing patient alleles of human galactose-1-phosphate uridylyltransferase. J Biol Chem. 2001 Apr 6;276(14):10634-40. PMID: 11152465 Wang BB et al. Molecular and biochemical basis of galactosemia. Mol Genet Metab. 1998 Apr;63(4):263-9. PMID: 9635294
Myriad Genetics, Inc.	RCV000003800	SCV001194025	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2019-11-15	criteria provided, single submitter	clinical testing	NM_000155.3(GALT):c.512T>C(F171S) is classified as likely pathogenic in the context of galactosemia. Sources cited for classification include the following: PMID 23583749, 23022339, 22944367, 10811638, 10960497, 11152465 and 1610789. Classification of NM_000155.3(GALT):c.512T>C(F171S) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses and is very rare or not present in genetic databases of healthy individuals. Please note: this variant was assessed in the context of healthy population screening.
GeneDx	RCV000723392	SCV001792432	pathogenic	not provided	2020-06-25	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a significant decrease in GALT enzyme activity (McCorvie et al., 2013; Crews et al., 2000; Riehman et al., 2001); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 9635294, 18956253, 23022339, 1301925, 10408771, 10535394, 11397328, 22944367, 1610789, 25124065, 22975760, 11152465, 27176039, 20008339, 10811638, 23583749, 8198125)
Baylor Genetics	RCV000003800	SCV004198521	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2024-03-25	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000723392	SCV004226590	pathogenic	not provided	2023-02-14	criteria provided, single submitter	clinical testing	PP3, PM2
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000003800	SCV004807356	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2024-03-26	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001831509	SCV004847529	pathogenic	Galactosemia	2023-11-17	criteria provided, single submitter	clinical testing	The p.Phe171Ser variant in GALT has been reported in the homozygous state in at least 2 individuals and in the compound heterozygous state with another disease causing variant in in GALT in 6 individuals with galactosemia (Reichardt 1992 PMID: 1610789, Palmieri 1999 PMID: 10535394, Velazquez-Aragon 2008 PMID: 18956253, Singh 2012 PMID: 23022339, Boutron 2012 PMID: 22944367, Garcia 2016 PMID: 27176039). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 3616) and has been identified in 0.01% (5/41434) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). In vitro functional studies provide evidence that this variant retains no enzymatic activity (Crews 2000 PMID: 10811638, McCorvie 2013 PMID: 23583749, Riehman 2001 PMID: 11152465) and computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive galactosemia. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_Moderate, PP3, PM2_Supporting, PP4.
OMIM	RCV000003800	SCV000023965	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	1992-06-23	no assertion criteria provided	literature only
Natera, Inc.	RCV001831509	SCV002085214	pathogenic	Galactosemia	2017-03-17	no assertion criteria provided	clinical testing