Variant chr9-34646575-CCAGT-C details in Genebe, Genetics Data Aggregator

Genes affected

GALT (HGNC:4135): (galactose-1-phosphate uridylyltransferase) Galactose-1-phosphate uridyl transferase (GALT) catalyzes the second step of the Leloir pathway of galactose metabolism, namely the conversion of UDP-glucose + galactose-1-phosphate to glucose-1-phosphate + UDP-galactose. The absence of this enzyme results in classic galactosemia in humans and can be fatal in the newborn period if lactose is not removed from the diet. The pathophysiology of galactosemia has not been clearly defined. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

GALT links:

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PP5

Variant 9-34646575-CCAGT-C is Pathogenic according to our data. Variant chr9-34646575-CCAGT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity, other]. Clinvar id is 25111.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=7, Uncertain_significance=1, other=1}.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0629 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALT	ENST00000605275.1 linkuse as main transcript	n.209-91_209-88del		intron_variant, non_coding_transcript_variant		3
GALT	ENST00000450095.6 linkuse as main transcript			upstream_gene_variant		2			P07902-2

Frequencies

GnomAD3 genomes

AF:

0.0471

AC:

7161

AN:

152148

Hom.:

258

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0125

Gnomad AMI

AF:

0.162

Gnomad AMR

AF:

0.0490

Gnomad ASJ

AF:

0.0481

Gnomad EAS

AF:

0.00943

Gnomad SAS

AF:

0.0690

Gnomad FIN

AF:

0.0672

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0645

Gnomad OTH

AF:

0.0440

GnomAD4 exome

AF:

0.0603

AC:

64222

AN:

1064534

Hom.:

2186

AF XY:

0.0610

AC XY:

33204

AN XY:

544444

show subpopulations

Gnomad4 AFR exome

AF:

0.0111

Gnomad4 AMR exome

AF:

0.0491

Gnomad4 ASJ exome

AF:

0.0510

Gnomad4 EAS exome

AF:

0.00640

Gnomad4 SAS exome

AF:

0.0758

Gnomad4 FIN exome

AF:

0.0679

Gnomad4 NFE exome

AF:

0.0636

Gnomad4 OTH exome

AF:

0.0570

GnomAD4 genome

AF:

0.0470

AC:

7163

AN:

152266

Hom.:

259

Cov.:

AF XY:

0.0468

AC XY:

3488

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0124

Gnomad4 AMR

AF:

0.0491

Gnomad4 ASJ

AF:

0.0481

Gnomad4 EAS

AF:

0.00926

Gnomad4 SAS

AF:

0.0689

Gnomad4 FIN

AF:

0.0672

Gnomad4 NFE

AF:

0.0645

Gnomad4 OTH

AF:

0.0445

Alfa

AF:

0.0553

Hom.:

Bravo

AF:

0.0422

Asia WGS

AF:

0.0340

AC:

118

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity; other

Submissions summary: Pathogenic:10Uncertain:1Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Pathogenic:5Benign:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 12, 2021	This variant occurs in a non-coding region of the GALT gene. It does not change the encoded amino acid sequence of the GALT protein. This variant is present in population databases (rs142496102, gnomAD 8%), including at least one homozygous and/or hemizygous individual. 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 an entry for this variant (Variation ID: 25111). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects GALT function (PMID: 11286503, 11479743, 19224951). For these reasons, this variant has been classified as Pathogenic. -
Benign, no assertion criteria provided	literature only	GeneReviews	Sep 23, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 03, 2022	The GALT c.-119_-116delGTCA variant (rs1275569312) is commonly found as part of the Duarte (D2) allele that is associated with mild decreases of GALT activity compared to the wildtype allele (Andersen 1984, Elsas 1994, Kozak 1999. Lai 1998, Langley 1997, Shin 1998). Functional characterization of the complex variant indicates a reduction in mRNA transcription due to the deletion in the promoter region (Elsas 2001, Trbusek 2001). Based on the above information, the variant is classified as mildly pathogenic. References: Andersen M et al. Transferase-deficiency galactosemia: immunochemical studies of the Duarte and Los Angeles variants. Hum Genet. 1984; 65(3):287-90. Elsas LJ et al. A common mutation associated with the Duarte galactosemia allele. Am J Hum Genet. 1994; 54(6):1030-6. Elsas LJ et al. Functional analysis of the human galactose-1-phosphate uridyltransferase promoter in Duarte and LA variant galactosemia. Genet Metab. 2001; 72(4):297-305. Kozak L et al. Presence of a deletion in the 5' upstream region of the GALT gene in Duarte (D2) alleles. J Med Genet. 1999; 36(7):576-8. Lai K et al. Duarte allele impairs biostability of galactose-1-phosphate uridyltransferase in human lymphoblasts.Hum Mutat. 1998; 11(1):28-38. Langley S et al. Molecular basis for Duarte and Los Angeles variant galactosemia. Am J Hum Genet. 1997; 60(2):366-72. Shin Y et al. Duarte-1 (Los Angeles) and Duarte-2 (Duarte) variants in Germany: two new mutations in the GALT gene which cause a GALT activity decrease by 40-50% of normal in red cells. J Inherit Metab Dis. 1998; 21(3):232-5. Trbusek M et al. Galactosemia: deletion in the 5' upstream region of the GALT gene reduces promoter efficiency. Hum Genet. 2001; 109(1):117-20. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Breda Genetics srl	Nov 09, 2021	The Duarte variant galactosemia is diagnosed in the presence of one heterozygous pathogenic GALT variant together with either a heterozygous or homozygous Duarte (D2) GALT variant. Five sequence changes in cis configuration are found on the Duarte variant (D2) allele. Of primary importance is the 4-bp deletion in the GALT promoter region (c.-119_-116delGTCA) that is considered to cause diminished transcription. The three remaining variants unique to D2 are c.378-27G>C, c.508-24G>A, and c.507+62G>A. The fifth sequence change is the missense variant c.940A>G (p.Asn314Asp); while always on the D2 allele, c.940A>G also occurs on other functionally normal GALT alleles (Fridovich-Keil et al., 2020, PMID: 25473725). -

not provided

Pathogenic:3Other:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	GALT: PM3:Very Strong, PM2:Supporting, PP4, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 28, 2023	- -
other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 23, 2018	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2022	The c.-119_-116delGTCA promoter variant (Duarte 2 variant) causes a reduction in GALT transcription resulting in approximately 50% of normal galactose-1-phosphate uridyltransferase (GALT) activity in individuals who are homozygous for this allele (Langley et al., 1997; Bosch et al., 2005; Carney et al., 2009); Common variant observed in 8% (278/3470) of alleles from individuals of European background (gnomAD); This variant is associated with the following publications: (PMID: 10424825, 11286503, 11479743, 19224951, 15841485, 10649501, 11754113, 25473725, 34030713) -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 15, 2023

The c.-119_-116delGTCA alteration is located in the 5' untranslated region (5'UTR) of the GALT gene. This alteration consists of a deletion of 4 nucleotides upstream from the first translated codon. ; however, this variant is known as the Duarte (D2) allele and is considered a mild allele associated with a biochemical phenotype. Based on data from gnomAD, the c.-119_-116delGTCA allele has an overall frequency of 4.889% (1533/31354) total alleles studied. The highest observed frequency was 8.012% (278/3470) of European (Finnish) alleles. This alteration is more common in population databases than expected for likely pathogenic/disease-causing variants (Pyhtila, 2015). This alteration is unique to the Duarte (D2) allele and is a cause of Duarte galactosemia, associated with a mild to asymptomatic phenotype. This alteration has been reported in asymptomatic individuals identified by newborn screening (Carney, 2009; Garcia, 2016). This nucleotide position is well conserved in available vertebrate species. Functional studies have shown that this deletion decreases GALT mRNA production and enzyme activity (Kozák, 1999; Elsas, 2001; Trbusek, 2001; Carney, 2009). In silico analysis was unable to predict the effect of this alteration. Based on the available evidence, this alteration is classified as pathogenic. -

Classical galactosemia, homozygous Duarte-type

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2009

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 15, 2022

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 0.046 in 150922 control chromosomes in the gnomAD database, including 242 homozygotes (gnomAD v3.1.2). Even though this frequency exceeds the maximal expected allele frequency for a pathogenic variant in GALT (0.0029), this variant is found in cis with 4 other (benign) variants as part of the Duarte 2 variant (D2) allele and it has been reported in the literature in multiple individuals with a biochemical diagnosis of Duarte galactosemia (DG) (e.g. 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 (Pasquali_2018, Fridovich-Keil_2020). 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 (Elsas_2001, Trbusek_2001, Carney_2009). 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). However, more recent publications put into question the clinical relevance of the D2 variant. Specifically, international clinical guidelines released by The Galactosemia Network (GalNet) recommend to not treat patients with the Duarte variant and to not provide endocrine follow-up, as there is no evidence that the ovaries are affected (Welling_2017). The authors review evidence from the literature reporting long-term outcomes in DG indicative of normal IQ scores, language skills, FSH values, and ophthalmologic examinations in untreated DG children aged 1-6 years (PMIDs: 18976948, 20489133) and comparable levels of FSH in female children with DG (up to 10.5 years) vs. healthy controls (PMID: 21719007). Nevertheless, Powell et al (PMID: 19904210) reported a higher percentage of children with DG enrolled in special education services compared to the general population, while a small pilot study identified some differences in socio-emotional development, in delayed recall, and in auditory processing speed between children with DG and their unaffected siblings (PMID: 25681083). Carlock et al (2019) and Fridovich-Keil et al (2021) conducted studies of dietary and developmental outcomes in children with DG (up to 12 years), and found no evidence of increased risk for acute complications or childhood developmental challenges that require intervention, regardless of milk exposure in infancy. Another study examined developmental outcomes and the need for special services in individuals with DG and concluded that Duarte-2 galactosemia may increase the risk for mild developmental delays during early infancy, but these are transient and dissipate with time (Waisbren_2021). Fridovich-Keil et al (2021) suggest based on their observations, that parents of infants diagnosed and treated for DG may be more motivated to seek special education services, which may explain the higher prevalence of this phenomenon in treated DG cases compared to their untreated DG counterparts. Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic, while one ClinVar submitter cites it as other. In conclusion, based on the evidence outlined above, and in particular the emergence of new evidence indicative of normal long-term outcomes for individuals with Duarte galactosemia, the variant was re-classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

chr9-34646575-CCAGT-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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