9-34649502-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000155.4(GALT):c.997C>T(p.Arg333Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000458 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R333L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

GALT
NM_000155.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 4.13

Variant links:

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:

ENSG00000258728 (HGNC:):

ENSG00000258728 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.957

PP5

Variant 9-34649502-C-T is Pathogenic according to our data. Variant chr9-34649502-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALT	NM_000155.4 link	c.997C>T	p.Arg333Trp	missense_variant	Exon 10 of 11	ENST00000378842.8	NP_000146.2	P07902-1B2RAT6A0A0S2Z3Y7
GALT	NM_001258332.2 link	c.670C>T	p.Arg224Trp	missense_variant	Exon 8 of 9		NP_001245261.1	P07902-2B2RAT6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALT	ENST00000378842.8 link	c.997C>T	p.Arg333Trp	missense_variant	Exon 10 of 11	1	NM_000155.4	ENSP00000368119.4		P07902-1
ENSG00000258728	ENST00000556278.1 link	c.432+1046C>T		intron_variant	Intron 4 of 7	5		ENSP00000451792.1		G3V4G9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251474

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000458

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000540

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Pathogenic:9

Apr 01, 2023

Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 13, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Lifecell International Pvt. Ltd

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 18, 2011

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

- -

Jul 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 333 of the GALT protein (p.Arg333Trp). This variant is present in population databases (rs111033800, gnomAD 0.003%). This missense change has been observed in individual(s) with classic or Duarte variant galactosemia (PMID: 1897530, 10384398, 10399107, 18207281, 25592817). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3610). 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 80%. Experimental studies have shown that this missense change affects GALT function (PMID: 1897530, 11152465, 12208137). For these reasons, this variant has been classified as Pathogenic. -

Jul 08, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Jul 31, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GALT c.997C>T; p.Arg333Trp variant (rs111033800) has been described in the compound heterozygous state in multiple individuals and families affected with classic or Duarte galactosemia (Ashino 1995, Carney 2009, Feillet 2008, Hirokawa 1999, Hughes 2009, Knerr 2013, Reichardt 1991, Viggiano 2015, Zaffanello 2005, Zekanowski 1999). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 3610), and is found in the general population with an overall allele frequency of 0.002% (5/246258 alleles) in the Genome Aggregation Database. In vitro functional studies of the variant protein demonstrates impaired GALT enzyme function (Reichardt 1991, Riehman 2001). Additionally, other variants at this codon (p.Arg333Gln, p.Arg333Gly, p.Arg333Leu) have been reported in individuals with galactosemia and are considered pathogenic (Leslie 1992, Ng 2003, Singh 2012, Tyfield 1999). Based on available information, the p.Arg333Trp variant is considered pathogenic. REFERENCES Ashino J et al. Molecular characterization of galactosemia (type 1) mutations in Japanese. Hum Mutat. 1995;6(1):36-43. Carney AE et al. Origins, distribution and expression of the Duarte-2 (D2) allele of galactose-1-phosphate uridylyltransferase. Hum Mol Genet. 2009 May 1;18(9):1624-32. Feillet F et al. Evidence of cataplerosis in a patient with neonatal classical galactosemia presenting as citrin deficiency. J Hepatol. 2008 Mar;48(3):517-22. Hirokawa H et al. Molecular basis for phenotypic heterogeneity in galactosaemia: prediction of clinical phenotype from genotype in Japanese patients. Eur J Hum Genet. 1999 Oct-Nov;7(7):757-64. Hughes J et al. Outcomes of siblings with classical galactosemia. J Pediatr. 2009 May;154(5):721-6. Knerr I et al. Leptin levels in children and adults with classic galactosaemia. JIMD Rep. 2013;9:125-131. Leslie N et al. The human galactose-1-phosphate uridyltransferase gene. Genomics. 1992 Oct;14(2):474-80. Ng W et al. Two adult galactosaemia females with normal ovarian function and identical GALT mutations (Q188R/R333G). J Inherit Metab Dis. 2003;26(1):75-9. Reichardt J et al. Molecular characterization of two galactosemia mutations: correlation of mutations with highly conserved domains in galactose-1-phosphate uridyl transferase. Am J Hum Genet. 1991 Oct;49(4):860-7. 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. Singh R et al. Biochemical and molecular characterization of GALT gene from Indian galactosemia patients: identification of 10 novel mutations and their structural and functional implications. Clin Chim Acta. 2012 Dec 24;414:191-6. Tyfield L et al. Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene. Hum Mutat. 1999;13(6):417-30. Viggiano E et al. Clinical and molecular spectra in galactosemic patients from neonatal screening in northeastern Italy: structural and functional characterization of new variations in the galactose-1-phosphate uridyltransferase (GALT) gene. Gene. 2015 Apr 1;559(2):112-8. Zaffanello M et al. Neonatal screening, clinical features and genetic testing for galactosemia. Genet Med. 2005 Mar;7(3):211-2. Zekanowski C et al. Molecular characterization of Polish patients with classical galactosaemia. J Inherit Metab Dis. 1999 Jun;22(5):679-82. -

Mar 07, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Sep 02, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 04, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies found this variant is associated with very low galactose-1-phosphate uridyl transferase activity compared to wild-type (PMID: 11152465, 1897530); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25087612, 10399107, 25592817, 10573007, 18207281, 8051928, 9686364, 10384398, 15775761, 11678552, 10408771, 15633893, 26419375, 20008339, 1897530, 19181333, 23430559, 2011574, 7550229, 19224951, 8892021, 8943248, 17143577, 8692963, 12208137, 18813948, 20663501, 22944367, 31589614, 7474913, 11152465, 25124065, 20547145, 21960482, 8522334, 25622686, 31194252, 34030713, 25174965, 8598637) -

Mar 25, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PP4, PM2, PM3, PS3 -

Galactosemia

Pathogenic:1

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

.;D

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.8

.;H

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-6.8

D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.86

MVP

1.0

MPC

0.34

ClinPred

1.0

GERP RS

4.3

Varity_R

0.95

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over