rs111033814
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000155.4(GALT):c.1030C>A(p.Gln344Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,614,072 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 (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
GALT
NM_000155.4 missense
NM_000155.4 missense
Scores
10
6
1
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000155.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
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MetaRNN computational evidence supports a deleterious effect, 0.912
PP5
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Variant 9-34649535-C-A is Pathogenic according to our data. Variant chr9-34649535-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 25320.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.1030C>A | p.Gln344Lys | missense_variant | 10/11 | ENST00000378842.8 | |
GALT | NM_001258332.2 | c.703C>A | p.Gln235Lys | missense_variant | 8/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GALT | ENST00000378842.8 | c.1030C>A | p.Gln344Lys | missense_variant | 10/11 | 1 | NM_000155.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152198Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461874Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727238
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152198Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3AN XY: 74352
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Pathogenic:6
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 03, 2021 | NM_000155.3(GALT):c.1030C>A(Q344K) is a missense variant classified as likely pathogenic in the context of galactosemia. Q344K has been observed in cases with relevant disease (PMID: 27363831, 21779791, 14728988, 11754113, Dobrowlski_2017_(no PMID; abstract)). Functional assessments of this variant are available in the literature (PMID: 23319291). Q344K has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, NM_000155.3(GALT):c.1030C>A(Q344K) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 22, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 19, 2023 | The GALT c.1030C>A; p.Gln344Lys variant (rs111033814) has been reported in patients diagnosed with hereditary galactosemia (Elsas 1998, Berry 2000, Yang 2002). This variant is also reported in ClinVar (Variation ID: 25320). It is only found on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. Codon 344 is located at the subunit interface and is predicted to be important for maintaining inter-subunit hydrogen bonds and stabilize the enzyme complex (Facchiano 2010). Functional characterization indicates that, when found in trans with another pathogenic GALT variant, the p.Gln344Lys variant abrogates GALT activity in erythrocytes (Berry 2000). Based on available information, this variant is considered to be pathogenic. References: Berry G et al. Galactose breath testing distinguishes variant and severe galactose-1-phosphate uridyltransferase genotypes. Pediatr Res. 2000; 48(3):323-8. PMID: 10960497. Elsas LJ et al. The molecular biology of galactosemia. Genet Med. 1998; 1(1):40-8. PMID: 11261429. Facchiano A et al. Analysis of galactosemia-linked mutations of GALT enzyme using a computational biology approach. Protein Eng Des Sel. 2010; 23(2):103-13. PMID: 20008339. Yang Y et al. Molecular analysis in newborns from Texas affected with galactosemia. Hum Mutat. 2002; 19(1):82-3. PMID: 11754113. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 14, 2022 | Variant summary: GALT c.1030C>A (p.Gln344Lys) results in a conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, C-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251468 control chromosomes. c.1030C>A has been reported in the literature in individuals affected with Galactosemia. These data indicate that the variant is 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 15, 2023 | This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 344 of the GALT protein (p.Gln344Lys). This variant is present in population databases (rs111033814, gnomAD 0.01%). This missense change has been observed in individual(s) with galactosemia (PMID: 11397328, 11754113; Invitae). ClinVar contains an entry for this variant (Variation ID: 25320). 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. Experimental studies have shown that this missense change affects GALT function (PMID: 23319291). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 27, 2016 | The Q344K missense change has been reported in patients with the severe galactosemia phenotype (Berry et al. 2000; Berry et al. 2004). The Q344K variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Q344K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (E340K, L342I, A345D) have been reported in the Human Gene Mutation Database in association with galactosemia (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we interpret Q344K to be likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 23, 2022 | PP3, PM2 - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Dec 04, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 07, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
T
PROVEAN
Uncertain
N;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
0.87
.;P
Vest4
MVP
MPC
0.26
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at