ClinVar Miner

Submissions for variant NM_000155.2(GALT):c.-119_-116delGTCA (rs111033640)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000022037 SCV000052459 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2019-09-26 criteria provided, single submitter clinical testing Variant summary: GALT c.-119_-116delGTCA involves the deletion of a stretch of four nucleotides located in the GALT promoter region. The variant allele was found at a frequency of 0.049 in 31354 control chromosomes, including 50 homozygotes (gnomAD). Even though this frequency exceeds the maximal expected allele frequency for a pathogenic variant in GALT (0.0029), multiple studies in affected individuals and functional assessments demonstrate the variant to be disease-associated. In particular, c.-119_-116delGTCA is found in cis with 4 other (benign) variants as part of the Duarte variant (D2) allele and it has been reported in the literature in multiple individuals affected with Duarte variant galactosemia (Elsas_2001, Yang_2002). This form of Galactosemia is caused by the presence of one heterozygous pathogenic GALT variant together with either a heterozygous or homozygous Duarte GALT variant, resulting in a reduction of GALT enzyme activity that is typically about 25% of normal activity (Fridovich-Keil_2019, Pasquali_2018). Experimental evidence evaluating an impact on protein function demonstrated c.-119_-116delGTCA to reduce promoter activity, causing diminished transcription of the gene eventually resulting in reduced GALT activity (Carney_2009, Elsas_2001, Trbusek_2001). The variant causes a milder effect on the enzyme activity than classic GALT pathogenic variants (carriers of the variant show about 75% of wild-type activity) (Elsas_2001). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV000185922 SCV000238877 pathogenic not provided 2018-12-04 criteria provided, single submitter clinical testing When c.-119_116delGTCA promoter mutation (Duarte-2 variant) is present on the same GALT allele (in cis) as the N314D, the result is an impaired regulatory domain of the GALT enzyme and approximately 50% of normal galactose-1-phosphate uridyltransferase (GALT) activity (Bosch et al., 2005). Newborns who are compound heterozygotes for the Duarte-2 variant (D" mutation) and a mutation associated with classic galactosemia ("G" mutation) are considered to have Duarte-2 variant galactosemia or D/G galactosemia which may be identified by newborn screening programs and is associated with approximately 50% of control galactosyltransferase activity, on average (Elsas, 2001)."
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000185922 SCV000858734 other not provided 2018-07-23 criteria provided, single submitter clinical testing
Invitae RCV000022037 SCV000959727 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2020-01-13 criteria provided, single submitter clinical testing This sequence change deletes 4 nucleotides (-119_-116delGTCA) in the GALT promoter without disrupting the protein coding sequence. This variant is present in population databases (rs111033640, 1KG 5.0%). This variant is unique to the D2 allele and is a well-known cause of Duarte galactosemia with a partial reduction, typically 14%-25% of wild-type GALT enzyme activity (PMID: 25473725). ClinVar contains two entries for this variant (Variation ID: 140570, 25111). Experimental studies have shown that this variant causes diminished GALT promoter activity in vitro and reduced GALT mRNA level in patient cells (PMID: 11286503, 11479743, 19224951). For these reasons, this sequence change has been classified as Pathogenic.
Mendelics RCV000022037 SCV001137799 likely pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2019-05-28 criteria provided, single submitter clinical testing
OMIM RCV000003809 SCV000023974 pathogenic Classical galactosemia, homozygous Duarte-type 2009-05-01 no assertion criteria provided literature only
Research and Development, ARUP Laboratories RCV000022037 SCV000042712 benign Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2012-12-04 no assertion criteria provided clinical testing Converted during submission to Benign.
GeneReviews RCV000022037 SCV000257439 benign Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2014-09-23 no assertion criteria provided literature only

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