rs111033802
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000155.4(GALT):c.983G>A(p.Arg328His) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. R328C) 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.983G>A | p.Arg328His | missense_variant | 10/11 | ENST00000378842.8 | |
GALT | NM_001258332.2 | c.656G>A | p.Arg219His | missense_variant | 8/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GALT | ENST00000378842.8 | c.983G>A | p.Arg328His | missense_variant | 10/11 | 1 | NM_000155.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152138Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251464Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135906
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461868Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727236
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152138Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74312
ClinVar
Submissions by phenotype
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 26, 2018 | Variant summary: GALT c.983G>A (p.Arg328His) results in a non-conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function, including one computational study that considers the Arg328 H-bond with Arg-51 essential for protein function (Facchiano_2009). The variant allele was found at a frequency of 4.1e-06 in 246246 control chromosomes (gnomAD). The variant, c.983G>A, has been reported in the literature in individuals affected with Galactosemia, including a homozygote (Ozgul_2013, Elsas_1998). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, with one lab calling it pathogenic in 2012. A different variant affecting the same codon, c.982C>T (p.Arg328Cys), was classified as likely pathogenic internally, suggesting this codon could play an important role in protein function. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 10, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 328 of the GALT protein (p.Arg328His). This variant is present in population databases (rs111033802, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of galactosemia (PMID: 33101984). ClinVar contains an entry for this variant (Variation ID: 25309). 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%. This variant disrupts the p.Arg328 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20663501). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Galactosemia Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at