Submissions for variant NM_000155.4(GALT):c.404C>T (p.Ser135Leu)

gnomAD frequency: 0.00094  dbSNP: rs111033690

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000003802	SCV000052464	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)	RCV000185915	SCV000110058	pathogenic	not provided	2018-07-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000185915	SCV000238868	pathogenic	not provided	2020-05-06	criteria provided, single submitter	clinical testing	Functional analysis found S135L is associated with significantly reduced enzyme activity (Fridovich-Keil et al., 1995; Coelho et al., 2014); In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect; This variant is associated with the following publications: (PMID: 1610789, 9323558, 12552079, 22975760, 25614870, 25087612, 11754113, 12208137, 12350230, 29302074, 34391645, 8551426, 11152465, 7887417, 20008339, 10070616, 19418241, 28065439, 27176039, 22944367, 22461411, 1373122, 31954591, 30275481, 34030713, 31589614)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000185915	SCV000280812	pathogenic	not provided	2014-11-18	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000003802	SCV000603781	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2023-08-15	criteria provided, single submitter	clinical testing	The GALT c.404C>T; p.Ser135Leu variant (rs111033690) has been reported in multiple individuals with GALT deficiency (Fridovich-Keil 1995, Lai 1996). Functional characterization of the variant protein indicates strongly reduced enzymatic activity and thermostability (Coelho 2014, Fridovich-Keil 1995, Lai 1996, Riehman 2001). This variant is also reported in ClinVar (Variation ID: 3618). It is observed in the general population with an overall allele frequency of 0.03% (94/282882 alleles) in the Genome Aggregation Database. The serine at codon 135 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.921). Based on available information, this variant is considered to be pathogenic. References: Coelho AI et al. Functional and structural impact of the most prevalent missense mutations in classic galactosemia. Mol Genet Genomic Med. 2014 Nov;2(6):484-96. PMID: 25614870. Fridovich-Keil JL et al. Identification and functional analysis of three distinct mutations in the human galactose-1-phosphate uridyltransferase gene associated with galactosemia in a single family. Am J Hum Genet. 1995 Mar;56(3):640-6. PMID: 7887417. Lai K et al. A prevalent mutation for galactosemia among black Americans. J Pediatr. 1996 Jan;128(1):89-95. PMID: 8551426. 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.
Fulgent Genetics, Fulgent Genetics	RCV000003802	SCV000611196	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2017-05-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000003802	SCV000755878	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 135 of the GALT protein (p.Ser135Leu). This variant is present in population databases (rs111033690, gnomAD 0.4%). This missense change has been observed in individual(s) with galactosemia (PMID: 7887417, 8551426, 12350230, 22461411, 22944367, 27176039, 28065439). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3618). 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: 7887417, 11152465, 12208137). For these reasons, this variant has been classified as Pathogenic.
SIB Swiss Institute of Bioinformatics	RCV000003802	SCV000803514	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Likely Pathogenic, for Galactosemia, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Present at frequency compatible with disease prevalence in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:11754113) (PMID:22461411). PS3 => Well-established functional studies show a deleterious effect (PMID:7887417,25614870).
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	RCV000003802	SCV000891572	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2024-06-12	criteria provided, single submitter	curation
Baylor Genetics	RCV000003802	SCV001163235	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2024-03-30	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000003802	SCV001194066	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2019-11-15	criteria provided, single submitter	clinical testing	NM_000155.3(GALT):c.404C>T(S135L) is classified as pathogenic in the context of galactosemia. Sources cited for classification include the following: PMID 10070616, 11754113, 19418241, 8551426, 7887417, 12208137, 1610789 and 11152465. Classification of NM_000155.3(GALT):c.404C>T(S135L) 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.
Revvity Omics, Revvity	RCV000003802	SCV002024165	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2020-12-14	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000003802	SCV002061793	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2021-12-28	criteria provided, single submitter	clinical testing	PS3, PP3, PM3_Strong
3billion	RCV000003802	SCV002521419	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.025%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003618). Different missense changes at the same codon (p.Ser135Pro, p.Ser135Trp) have been reported to be associated with GALT related disorder (ClinVar ID: VCV000025172 / PMID: 15841485, 22944367). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251865	SCV002523875	pathogenic	See cases	2020-11-27	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3, PS4, PM2, PM3, PP3
Mayo Clinic Laboratories, Mayo Clinic	RCV000185915	SCV002525787	pathogenic	not provided	2023-06-13	criteria provided, single submitter	clinical testing
DASA	RCV000003802	SCV002526404	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2022-06-10	criteria provided, single submitter	clinical testing	The c.404C>T;p.(Ser135Leu) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 3618; PMID: 20301691; 28065439; 27176039; 10070616; 7887417) - PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 9323558) - PS3_supporting. The variant is present at low allele frequencies population databases (rs111033690– gnomAD 0.009002%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Ser135Leu) was detected in trans with a Pathogenic variant (PMID: 28065439; 27176039; 10070616) - PM3_strong. Pathogenic missense variant in this residue have been reported and classified as Pathogenic by ACMG criteria (Clinvar ID: 25172) -PM5. 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
Ambry Genetics	RCV002512724	SCV003549281	pathogenic	Inborn genetic diseases	2021-06-23	criteria provided, single submitter	clinical testing	The c.404C>T (p.S135L) alteration is located in exon 5 (coding exon 5) of the GALT gene. This alteration results from a C to T substitution at nucleotide position 404, causing the serine (S) at amino acid position 135 to be replaced by a leucine (L). Based on data from the Genome Aggregation Database (gnomAD) database, the GALT c.404C>T alteration was observed in 0.03% (94/282882) of total alleles studied, with a frequency of 0.35% (87/24960) in the African subpopulation. This mutation has been reported in multiple individuals in the homozygous and compound heterozygous states with galactosemia (Henderson, 2002; Boutron, 2012; Garcia, 2016; Welsink-Karssies, 2020). In yeast and E. coli, GALT activity was reduced compared to wild type (Fridovich-Keil, 1995; Riehman, 2001; Coelho, 2014). The p.S135L alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000003802	SCV004804835	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2024-03-17	criteria provided, single submitter	research
OMIM	RCV000003802	SCV000023967	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	1996-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000003802	SCV000147993	not provided	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase		no assertion provided	literature only	Most common clinical pathogenic variant in African Americans & South Africans
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000003802	SCV001133119	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2019-09-26	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001826412	SCV002085200	pathogenic	Galactosemia	2017-03-17	no assertion criteria provided	clinical testing
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV000003802	SCV003927842	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2023-04-01	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004752682	SCV005352059	pathogenic	GALT-related disorder	2024-04-24	no assertion criteria provided	clinical testing	The GALT c.404C>T variant is predicted to result in the amino acid substitution p.Ser135Leu. This variant has been well documented to be causative for galactosemia and is particularly common among individuals of African descent (Fridovich-Keil et al. 1995. PubMed ID: 7887417; Ya et al. 2002. PubMed ID: 11754113). Consistent with this observation, the c.404C>T variant has been observed at an allele frequency of ~0.35% in an African population in a large database, whereas it is present at <0.02% in other populations in the same database (http://gnomad.broadinstitute.org/variant/9-34647855-C-T). In functional assays, the activity of the GALT enzyme carrying the p.Ser135Leu substitution has been shown to be significantly reduced (Fridovich-Keil et al. 1995. PubMed ID: 7887417; Ya et al. 2002. PubMed ID: 11754113). In red blood cells from patients homozygous for the c.404C>T (p.Ser135Leu) variant, GALT enzyme activity is typically absent. However, ~10% enzyme activity remains in other tissues. As a result, patients homozygous for this variant may go undetected by newborn screening (Crushell et al. 2009. PubMed ID: 19418241). For these reasons, the p.Ser135Leu substitution has been associated with a form of galactosemia referred to as clinical variant galactosemia (see Berry 2017. PubMed ID: 20301691 for further details on clinical variant galactosemia). We classify this variant as pathogenic.