rs111033695
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000155.4(GALT):c.425T>A(p.Met142Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,614,190 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. M142V) 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 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GALT | NM_000155.4 | c.425T>A | p.Met142Lys | missense_variant | 5/11 | ENST00000378842.8 | |
GALT | NM_001258332.2 | c.98T>A | p.Met33Lys | missense_variant | 3/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GALT | ENST00000378842.8 | c.425T>A | p.Met142Lys | missense_variant | 5/11 | 1 | NM_000155.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251496Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135922
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461892Hom.: 0 Cov.: 33 AF XY: 0.0000179 AC XY: 13AN XY: 727246
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152298Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74478
ClinVar
Submissions by phenotype
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Pathogenic:6
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 1991 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 02, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 16, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 29, 2023 | This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 142 of the GALT protein (p.Met142Lys). This variant is present in population databases (rs111033695, gnomAD 0.004%). This missense change has been observed in individual(s) with galactosemia (PMID: 2011574, 10384398, 10960497, 17041746, 20213376, 22944367, 23924834). ClinVar contains an entry for this variant (Variation ID: 3609). 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. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 23, 2021 | Variant summary: GALT c.425T>A (p.Met142Lys) results in a non-conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251496 control chromosomes. c.425T>A has been reported in the literature in multiple individuals affected with Galactosemia, both in the homozygous and compound heterozygous state (Reichardt_1991, Shin_1999, Milankovics_2010, Seyrantepe_1999, Bosch_2005, Gort_2006, Boutron_2012, etc). The variant has been reported to have <10% wild-type enzyme activity when expressed in COS cells (Reichardt_1991). Three 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. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 04, 2022 | Expression of M142K in COS cells was associated with a severe reduction in galactose-1-phosphate uridyltransferase (GALT) enzyme activity compared to wild type (Reichardt et al. 1991); Not observed at 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: 22944367, 17041746, 20008339, 10960497, 20213376, 31194252, 31980526, 34030713, 31589614, 10384398, 2011574) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 14, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | GALT: PM3:Very Strong, PM1, PM2, PM5, PP3, PS3:Supporting - |
GALT-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 24, 2022 | The GALT c.425T>A variant is predicted to result in the amino acid substitution p.Met142Lys. This variant has previously been reported in the homozygous state or with a second pathogenic GALT variant in multiple patients with classic galactosemia (e.g., Reichardt et al. 1991. PubMed ID 2011574; Shin et al. 1999. PubMed ID 10384398; Boutron et al. 2012, PMID 22944367). The p.Met142Lys substitution was reported to abolish GALT enzyme activity in a functional study using COS cells (Reichardt et al. 1991. PubMed ID 2011574). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-34647876-T-A). It is interpreted as a pathogenic variant but multiple independent submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/3609/). Taken together, we interpret this variant as pathogenic. - |
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