rs111033692
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000155.4(GALT):āc.424A>Gā(p.Met142Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,894 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 (ā ā ). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M142K) has been classified as Pathogenic.
Frequency
Consequence
NM_000155.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GALT | NM_000155.4 | c.424A>G | p.Met142Val | missense_variant | 5/11 | ENST00000378842.8 | |
GALT | NM_001258332.2 | c.97A>G | p.Met33Val | missense_variant | 3/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GALT | ENST00000378842.8 | c.424A>G | p.Met142Val | missense_variant | 5/11 | 1 | NM_000155.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461894Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727248
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 20, 2023 | Variant summary: GALT c.424A>G (p.Met142Val) results in a conservative amino acid change located in the N-terminal domain (IPR005849) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251496 control chromosomes. c.424A>G has been reported in the literature in at least one compound heterozygous individual affected with Galactosemia (e.g., Hirokawa_1999). These data suggest the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 11% of normal activity in a COS cell expression system (Hirokawa_1999). The following publication was ascertained in the context of this evaluation (PMID: 10573007). No submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Additionally, other missense variants affecting the same codon, namely c.425T>A (p.Met142Val) and c.425T>C (p.Met142Thr), have been classified as pathogenic by our lab or reported in ClinVar as pathogenic. Both of these additional missense variants have been reported in the literature in patients affected with galactosemia (PMIDs: 15775761, 25592817, 2011574, 10384398) and studies have found these variants result in <5% GALT activity either experimentally or in erythrocytes from patients harboring these variants (PMIDs: 25592817, 2011574), suggesting this residue is clinically significant. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 23, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met142 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2011574, 10384398, 10960497, 20213376). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects GALT function (galactosemia). 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. This missense change has been observed in individual(s) with galactosemia (PMID: 10573007). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 142 of the GALT protein (p.Met142Val). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at