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

Total submissions: 13

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
Counsyl	RCV000003802	SCV000485248	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2016-07-19	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	2019-01-09	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
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