Submissions for variant NM_000155.4(GALT):c.584T>C (p.Leu195Pro)

gnomAD frequency: 0.00006  dbSNP: rs111033728

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000022158	SCV000052469	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
Eurofins Ntd Llc (ga)	RCV000224416	SCV000110068	pathogenic	not provided	2015-09-18	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224416	SCV000280877	pathogenic	not provided	2015-09-14	criteria provided, single submitter	clinical testing
Invitae	RCV000022158	SCV000818252	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 195 of the GALT protein (p.Leu195Pro). This variant is present in population databases (rs111033728, gnomAD 0.02%). This missense change has been observed in individual(s) with galactosemia (PMID: 1373122, 8598637, 10649501, 19375122, 22944367). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 25222). 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: 1373122). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000022158	SCV000893810	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2022-05-11	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000022158	SCV001160717	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2022-04-21	criteria provided, single submitter	clinical testing	The GALT c.584T>C; p.Leu195Pro variant (rs111033728), is reported in the literature in the compound heterozygous state with known pathogenic GALT variants in multiple individuals affected with mild to severe galactosemia (Boutron 2012, Kozak 2000, Reichardt 1992). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 25222), and is found in the non-Finnish European population with an allele frequency of 0.015% (17/113,764 alleles) in the Genome Aggregation Database. The leucine at codon 195 is moderately conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. However, functional analyses of the variant protein show reduced GALT enzymatic activity in vitro (Reichardt 1992). Based on available information, the p.Leu195Pro variant is considered to be pathogenic. References: Boutron A et al. Mutation spectrum in the French cohort of galactosemic patients and structural simulation of 27 novel missense variations. Mol Genet Metab. 2012 Nov;107(3):438-47. Kozak L et al. Mutation analysis of the GALT gene in Czech and Slovak galactosemia populations: identification of six novel mutations, including a stop codon mutation (X380R). Hum Mutat. 2000 Feb;15(2):206. Reichardt JK et al. Characterization of two missense mutations in human galactose-1-phosphate uridyltransferase: different molecular mechanisms for galactosemia. Genomics. 1992 Mar;12(3):596-600.
Baylor Genetics	RCV000022158	SCV001163240	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000022158	SCV001194049	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2019-12-09	criteria provided, single submitter	clinical testing	NM_000155.3(GALT):c.584T>C(L195P) is classified as pathogenic in the context of galactosemia. Sources cited for classification include the following: PMID 19375122, 1373122, 8598637, 10649501, 10960497, 15841485 and 11397328. Classification of NM_000155.3(GALT):c.584T>C(L195P) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.‚Äã
CeGaT Center for Human Genetics Tuebingen	RCV000224416	SCV001246076	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	GALT: PM3:Strong, PM1, PM2, PP4, PS3:Supporting
GeneDx	RCV000224416	SCV001769942	pathogenic	not provided	2022-02-28	criteria provided, single submitter	clinical testing	A common variant that has been estimated to represent approximately 2% of GALT mutant alleles in the US (Elsas et al., 1998); Published functional studies demonstrate a damaging effect (Reichardt et al. 1992); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10649501, 27415407, 11261429, 27604308, 22975760, 20008339, 17041746, 1373122, 22944367, 8598637, 31194252, 31954591, 34030713, 31589614)
DASA	RCV000022158	SCV002526410	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2022-06-10	criteria provided, single submitter	clinical testing	The c.584T>C;p.(Leu195Pro) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 25222; PMID: 22944367; 20301691; 19375122) - PS4. The variant is present at low allele frequencies population databases (rs111033728– gnomAD 0.0005256%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Leu195Pro) was detected in trans with a Pathogenic variant (PMID: 22944367; 19375122) - PM3_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic
Genetics and Molecular Pathology, SA Pathology	RCV000022158	SCV002556549	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2021-05-21	criteria provided, single submitter	clinical testing
GeneReviews	RCV000022158	SCV000147996	not provided	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase		no assertion provided	literature only	Severe classic pathogenic variant
Natera, Inc.	RCV001826496	SCV002085219	pathogenic	Galactosemia	2017-03-17	no assertion criteria provided	clinical testing