ClinVar Miner

Submissions for variant NM_000155.4(GALT):c.404C>T (p.Ser135Leu) (rs111033690)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000003802 SCV000052464 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 RCV000185915 SCV000110058 pathogenic not provided 2018-07-19 criteria provided, single submitter clinical testing
GeneDx RCV000185915 SCV000238868 pathogenic not provided 2018-07-27 criteria provided, single submitter clinical testing The S135L variant in the GALT gene is a common pathogenic variant in African Americans,accounting for approximately 50% of pathogenic GALT alleles in this population and has beenassociated with classic galactosemia when present with a pathogenic GALT variant associated withclassic galactosemia on the opposite allele (in trans) and with clinical variant galactosemia whenhomozygous (Dobrowolski et al., 2003; Bosch et al., 2005; Berry 2017). Functional analysis of S135Lfound that it is associated with significantly reduced enzyme activity (Fridovich-Keil et al., 1995;Coelho et al., 2014). We interpret S135L to be a pathogenic variant.
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 RCV000185915 SCV000603781 pathogenic not provided 2018-03-14 criteria provided, single submitter clinical testing The GALT c.404C>T, p.Ser135Leu variant has been reported in multiple patients with GALT deficiency, and the variant protein has reduced enzymatic activity (Coelho 2014, Fridovich-Keil 1995, Lai 1996, Riehman 2001). References: 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. Fridovich-Keil J 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; 56(3):640-6. Lai K et al. A prevalent mutation for galactosemia among black Americans. J Pediatr. 1996; 128(1):89-95. 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; 276(14):10634-40.
Fulgent Genetics,Fulgent Genetics RCV000003802 SCV000611196 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000003802 SCV000755878 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 135 of the GALT protein (p.Ser135Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs111033690, ExAC 0.4%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in multiples individuals affected with galactosemia (PMID: 7887417, 28065439, 22944367, 22461411, 27176039) and it is known to be a prevalent galactosemia variant in African and African American populations (PMID: 8551426, 12350230). ClinVar contains an entry for this variant (Variation ID: 3618). Experimental studies have shown that this missense change severely reduces GALT enzymatic activity by disrupting protein subunits assembly (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, Oman RCV000003802 SCV000891572 likely pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2017-12-30 criteria provided, single submitter curation
Baylor Genetics RCV000003802 SCV001163235 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase criteria provided, single submitter clinical testing
Myriad Women's Health, 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.
OMIM RCV000003802 SCV000023967 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 1996-01-01 no assertion criteria provided literature only
Research and Development, ARUP Laboratories RCV000003802 SCV000042781 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2012-12-04 no assertion criteria provided clinical testing Converted during submission to Pathogenic.
GeneReviews RCV000003802 SCV000147993 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2014-04-03 no assertion criteria provided literature only
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

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