Submissions for variant NM_000155.4(GALT):c.855G>T (p.Lys285Asn) (rs111033773)

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	RCV000003805	SCV000052475	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000224446	SCV000110077	pathogenic	not provided	2018-06-12	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics	RCV000224446	SCV000281425	pathogenic	not provided	2015-09-14	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV000003805	SCV000603795	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2020-07-07	criteria provided, single submitter	clinical testing	The GALT c.855G>T; p.Lys285Asn variant (rs111033773) is reported in multiple individuals diagnosed with classic galactosemia when found in trans with another pathogenic variant (Chhay 2008, Viggiano 2015). Functional characterization of the variant protein in red blood cells and yeast cells indicates severe reduction in GALT activity (Chhay 2008, Coelho 2014, Viggiano 2015). This variant is reported as pathogenic in ClinVar (Variation ID: 3621). It is found in the general population with an overall allele frequency of 0.01% (36/282874 alleles) in the Genome Aggregation Database. The lysine at codon 285 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, the variant is considered to be pathogenic. REFERENCES Chhay J et al. A yeast model reveals biochemical severity associated with each of three variant alleles of galactose-1P uridylyltransferase segregating in a single family. J Inherit Metab Dis. 2008; 31(1):97-107. Coelho A et al. Functional and structural impact of the most prevalent missense mutations in classic galactosemia. Mol Genet Genomic Med. 2014; 2(6):484-96. Viggiano E et al. Clinical and molecular spectra in galactosemic patients from neonatal screening in northeastern Italy: structural and functional characterization of new variations in the galactose-1-phosphate uridyltransferase (GALT) gene. Gene. 2015; 559(2):112-8.
Invitae	RCV000003805	SCV000813007	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2020-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces lysine with asparagine at codon 285 of the GALT protein (p.Lys285Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is present in population databases (rs111033773, ExAC 0.03%). This variant has been observed in individuals with low GALT enzyme activity, findings that are highly specific for galactose-1-phosphate uridylyltransferase deficiency (PMID: 18210213, 25592817, 16540753, Invitae). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in individuals affected with galactose-1-phosphate uridylyltransferase deficiency (PMID: 25592817, 16540753, Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 3621). Experimental studies have shown that this missense change results in a GALT protein with null enzymatic activity (PMID: 18210213, 11152465, 25614870). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics	RCV000003805	SCV000894465	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2018-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000003805	SCV001163247	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase		criteria provided, single submitter	clinical testing
Myriad Women's Health, Inc.	RCV000003805	SCV001193981	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2019-11-11	criteria provided, single submitter	clinical testing	NM_000155.3(GALT):c.855G>T(K285N) is classified as pathogenic in the context of galactosemia. Sources cited for classification include the following: PMID 10649501, 9222760, 11152465, and 18210213. Classification of NM_000155.3(GALT):c.855G>T(K285N) 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.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000224446	SCV001246077	pathogenic	not provided	2018-08-01	criteria provided, single submitter	clinical testing
Breda Genetics srl	RCV000003805	SCV001371685	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2020-03-31	criteria provided, single submitter	clinical testing	The variant c.855G>T (p.Lys285Asn) is reported as pathogenic for galactosemia in ClinVar (Variation ID: 3621) and as affecting function/effect unknown in the Global Variome shared LOVD database v.3.0. In one study, this variant has been identified in homozygous state in 3 unrelated children and in compound heterozygous state with a second mutation in 12 children with classical galactosemia from unrelated families. The cohort of patients included families from Austria, Croatia and Germany. GALT activity in erythrocyte lysates of the three homozygous patients was reduced to 0.5 +- 2.41 mmol/hr/gHb (mean +- SD, normal 27.8 +- 6 mmol/hr/g Hb). The mean GALT activity determined in compound heterozygous patients was 0.5 +- 0.43 mmol/ hr/gHb (mean +- SD). In both homozygotes and compound heterozygotes, the clinical course in the newborn period was severe including jaundice, hepatomegaly, failure to thrive, cataracts, neurological symptoms, and cerebral edema. For most of them intensive care, including exchange transfusions, was necessary. According to the authors, this variant is a common mutation in their population (Greber-Platzer et al., 1997, PMID: 9222760). The variant is reported with an estimated allele frequency of 0.0002 in 1000 Genomes Project, 0.0001392 in gnomAD exomes, and 0.00003186 in gnomAD genomes, with no homozygous individuals reported.
OMIM	RCV000003805	SCV000023970	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	1997-01-01	no assertion criteria provided	literature only
Research and Development, ARUP Laboratories	RCV000003805	SCV000042903	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2012-12-04	no assertion criteria provided	clinical testing	Converted during submission to Pathogenic.
GeneReviews	RCV000003805	SCV000147999	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2021-03-09	no assertion criteria provided	literature only	Most severe classic pathogenic variant in eastern Europe
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000224446	SCV001807579	pathogenic	not provided		no assertion criteria provided	clinical testing