rs111033773
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000155.4(GALT):c.855G>T(p.Lys285Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,614,162 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K285R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000155.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000164 AC: 25AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000139 AC: 35AN: 251490Hom.: 0 AF XY: 0.000147 AC XY: 20AN XY: 135922
GnomAD4 exome AF: 0.000178 AC: 260AN: 1461864Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 127AN XY: 727230
GnomAD4 genome AF: 0.000164 AC: 25AN: 152298Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74474
ClinVar
Submissions by phenotype
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Pathogenic:13Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1997 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 22, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 16, 2020 | - - |
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 | Myriad Genetics, Inc. | Nov 11, 2019 | NM_000155.3(GALT):c.855G>T(K285N) is classified as pathogenic in the context of galactosemia. Sources cited for classification include the following: PMID 10649501, 9222760, 11152465, and 18210213. Classification of NM_000155.3(GALT):c.855G>T(K285N) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 14, 2023 | The GALT c.855G>T (p.Lys285Asn) missense variant is a well-established disease-causing variant which has been reported in many individuals with galactosemia in the peer-reviewed literature (GeneReviews PMID: 20301691). Functional studies and computational evidence support the variant's damaging effect on the GALT enzyme (PMID: 9222760). The highest frequency of this allele in the Genome Aggregation Database is 0.000338 in the European (non-Finnish) population (version 3.1.2). The c.855G>T variant has been classified as pathogenic by over 15 submitters in ClinVar. This variant was identified in trans with a likely pathogenic variant. Based on the available evidence, the c.855G>T (p.Lys285Asn) variant is classified as pathogenic for galactosemia. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 23, 2024 | This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 285 of the GALT protein (p.Lys285Asn). This variant is present in population databases (rs111033773, gnomAD 0.02%). This variant has been observed in individuals with low GALT enzyme activity, findings that are highly specific for galactose-1-phosphate uridylyltransferase deficiency (PMID: 18210213, 25592817, 16540753, internal data). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in individuals affected with galactose-1-phosphate uridylyltransferase deficiency (PMID: 25592817, 16540753, internal data). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 3621). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 11152465, 18210213, 25614870). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Breda Genetics srl | Mar 31, 2020 | The variant c.855G>T (p.Lys285Asn) is reported as pathogenic for galactosemia in ClinVar (Variation ID: 3621) and as affecting function/effect unknown in the Global Variome shared LOVD database v.3.0. In one study, this variant has been identified in homozygous state in 3 unrelated children and in compound heterozygous state with a second mutation in 12 children with classical galactosemia from unrelated families. The cohort of patients included families from Austria, Croatia and Germany. GALT activity in erythrocyte lysates of the three homozygous patients was reduced to 0.5 +- 2.41 mmol/hr/gHb (mean +- SD, normal 27.8 +- 6 mmol/hr/g Hb). The mean GALT activity determined in compound heterozygous patients was 0.5 +- 0.43 mmol/ hr/gHb (mean +- SD). In both homozygotes and compound heterozygotes, the clinical course in the newborn period was severe including jaundice, hepatomegaly, failure to thrive, cataracts, neurological symptoms, and cerebral edema. For most of them intensive care, including exchange transfusions, was necessary. According to the authors, this variant is a common mutation in their population (Greber-Platzer et al., 1997, PMID: 9222760). The variant is reported with an estimated allele frequency of 0.0002 in 1000 Genomes Project, 0.0001392 in gnomAD exomes, and 0.00003186 in gnomAD genomes, with no homozygous individuals reported. - |
not provided, no classification provided | literature only | GeneReviews | - | Most severe classic pathogenic variant in eastern Europe - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | May 14, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Sep 08, 2021 | - - |
Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 21, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 19, 2024 | The GALT c.855G>T; p.Lys285Asn variant (rs111033773) is reported in multiple individuals diagnosed with classic galactosemia when found in trans with another pathogenic variant (Chhay 2008, Viggiano 2015). Functional characterization of the variant protein in red blood cells and yeast cells indicates severe reduction in GALT activity (Chhay 2008, Coelho 2014, Viggiano 2015). This variant is reported as pathogenic in ClinVar (Variation ID: 3621). It is found in the general population with an overall allele frequency of 0.01% (36/282874 alleles) in the Genome Aggregation Database. The lysine at codon 285 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.883). Based on available information, the variant is considered to be pathogenic. References: Chhay J et al. A yeast model reveals biochemical severity associated with each of three variant alleles of galactose-1P uridylyltransferase segregating in a single family. J Inherit Metab Dis. 2008; 31(1):97-107. PMID: 18210213. Coelho A et al. Functional and structural impact of the most prevalent missense mutations in classic galactosemia. Mol Genet Genomic Med. 2014; 2(6):484-96. PMID: 25614870. 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; 559(2):112-8. PMID: 25592817. - |
not provided Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 12, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 05, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 17, 2020 | Second most common galactosemia-associated variant among people of European ancestry (Tyfield et al., 1999); Published functional studies demonstrate a damaging effect with absent GALT enzyme activity in purified recombinant human protein studies and when expressed in yeast (Coelho et al., 2014; Riehman et al., 2001); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10220154, 25087612, 22975760, 11152465, 18210213, 25614870, 20008339, 21228398, 1427861, 11754113, 10408771, 16540753, 9222760, 10399107, 25592817, 10649501, 29252199, 30994193, 31194252, 31954591, 31980526, 34030713, 31589614) - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Sep 14, 2015 | - - |
Galactosemia Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at