rs111033694

chr9-34647897-G-A

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.443G>A(p.Arg148Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,614,038 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. R148W) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: GALT NM_000155.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 4.29

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 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr9-34647896-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 37359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 9-34647897-G-A is Pathogenic according to our data. Variant chr9-34647897-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 25178.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.443G>A	p.Arg148Gln	missense_variant	5/11	ENST00000378842.8
GALT	NM_001258332.2	c.116G>A	p.Arg39Gln	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALT	ENST00000378842.8	c.443G>A	p.Arg148Gln	missense_variant	5/11	1	NM_000155.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251482 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461888 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74322

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 12, 2018	Variant summary: GALT c.443G>A (p.Arg148Gln) results in a conservative amino acid change located in the N-terminal of the Galactose-1-phosphate uridyl transferase, of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 246264 control chromosomes in gnomAD. This frequency is not significantly higher than expected for a pathogenic variant in GALT causing Galactosemia (2.8e-05 vs 2.90E-03), allowing no conclusion about variant significance. The variant, c.443G>A, has been reported in the literature in multiple individuals affected with Galactosemia (Elsas_1995, Bosch_2005, Gort_2009, Boutron_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 20, 2021	The GALT c.443G>A p(.Arg148Gln) missense variant has been identified in individuals with a phenotype consistent with galactosemia, including at least one in a homozygous state and one in a compound heterozygous state (Elsas et al. 1995; Bosch et al. 2005; Gort et al. 2006; Boutron et al. 2012). The highest frequency of this allele in the Genome Aggregation Database is 0.000145 in the Latino/Admixed American population (version 2.1.1). The c.443G>A variant lies within the galactose-1-phosphate uridyl transferase, N-terminal domain, in which multiple missense variants have been previously reported as likely pathogenic or pathogenic for galactosemia. Computational modeling predicts damaging effect of the variant on GALT function, and in vitro studies showed that the p.Arg148Gln change results in undetectable enzyme activity (Facchiano and Marabotti 2010; Coelho et al. 2014). Additionally, an alternative amino acid change at the same position, the p.Arg148Trp, has been reported in individuals affected with galactosemia (Elsas et al. 1995; Bosch et al. 2005; Boutron et al. 2012). Based on the available evidence, the c.443G>A p.(Arg148Gln) variant is classified as pathogenic for galactosemia. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	A heterozygous missense variant was identified, NM_000155.3(GALT):c.443G>A in exon 5 of 11 of the GALT gene. This substitution is predicted to create a minor amino acid change from arginine to glutamine at position 148 of the protein, NP_000146.2(GALT):p.(Arg148Gln). The arginine at this position has moderate conservation (100 vertebrates, UCSC), and is located within the GalP_UDP_transf functional domain. In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.0024% (6 heterozygotes, 0 homozygotes). The variant has been previously reported pathogenic in multiple patients with galactosemia (ClinVar, Boutron, A. et al . (2012), Gort, L. et al . (2006)). In addition, functional studies show that this variant results in null enzyme activity (Coelho, A. I. et al. (2014)). Different variants in the same codon resulting in changes to tryptophan, glycine and proline have also been shown to cause galactosemia (ClinVar, Barbouth, D. S. et al. (2007)). Analysis of parental samples indicated this variant was maternally inherited. Based on information available at the time of curation, this variant has been classified as PATHOGENIC. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 10, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 148 of the GALT protein (p.Arg148Gln). This variant is present in population databases (rs111033694, gnomAD 0.01%). This missense change has been observed in individuals with galactosemia (PMID: 7887416, 15841485, 19375122, 22944367). ClinVar contains an entry for this variant (Variation ID: 25178). 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 95%. Experimental studies have shown that this missense change affects GALT function (PMID: 25614870). This variant disrupts the p.Arg148 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1373122, 7887416, 15841485, 22944367, 25268296). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 10, 2017	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2019	Expression studies found that the R148Q variant was associated with GALT enzyme activity below the limits of detection (Coelho et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31589614, 31980526, 7887416, 25614870, 25525159, 20008339) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 27, 2014	- -

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	Benign	0.11
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Uncertain	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.2	D
MutationTaster	Benign	1.0	A;A
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.3	N;N
REVEL	Uncertain	0.64
Sift	Benign	0.15	T;T
Sift4G	Benign	0.50	T;T
Polyphen		0.71	.;P
Vest4		0.86
MutPred		0.88		.;Gain of catalytic residue at R148 (P = 0.1179);
MVP		0.98
MPC		1.9
ClinPred		0.31	T
GERP RS		5.3
Varity_R		0.54
gMVP		0.82

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: rs111033694; hg19: chr9-34647894;