9-34649502-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_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. R333G) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: GALT NM_000155.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 4.13

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000155.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-34649502-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 3623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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/exons	MANE	UniProt
GALT	NM_000155.4	c.997C>T	p.Arg333Trp	missense_variant	10/11	ENST00000378842.8
GALT	NM_001258332.2	c.670C>T	p.Arg224Trp	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALT	ENST00000378842.8	c.997C>T	p.Arg333Trp	missense_variant	10/11	1	NM_000155.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000278 AC: 7 AN: 251474 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135916

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: 67 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 30 AN XY: 727240

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.: 31

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Pathogenic:9

Pathogenic, no assertion criteria provided	clinical testing	Lifecell International Pvt. Ltd	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 05, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 13, 1996	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jul 08, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	Apr 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 31, 2018	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. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 02, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 28, 2021	PS3, PS4_moderate, PM2, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2021	Published functional studies demonstrate very low galactose-1-phosphate uridyl transferase activity compared to wild-type (Riehman et al., 2001; Reichardt et al. 1991); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 31589614, 31194252, 25124065, 25174965, 26419375, 15633893, 22944367, 10408771, 11678552, 25622686, 20663501, 21960482, 8598637, 18813948, 8522334, 15775761, 20547145, 7474913, 10384398, 9686364, 8051928, 12208137, 23430559, 19181333, 18207281, 8692963, 17143577, 10573007, 8943248, 8892021, 19224951, 10399107, 7550229, 2011574, 1897530, 20008339, 11152465, 25592817, 25087612) -

Galactosemia Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 17, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
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	D
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

Other links and lift over

dbSNP: rs111033800; hg19: chr9-34649499;