rs786204763
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000155.4(GALT):c.775C>T(p.Arg259Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,022 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic 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. R259Q) 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.775C>T | p.Arg259Trp | missense_variant | 8/11 | ENST00000378842.8 | |
GALT | NM_001258332.2 | c.448C>T | p.Arg150Trp | missense_variant | 6/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GALT | ENST00000378842.8 | c.775C>T | p.Arg259Trp | missense_variant | 8/11 | 1 | NM_000155.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250824Hom.: 1 AF XY: 0.0000221 AC XY: 3AN XY: 135666
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461022Hom.: 1 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 726872
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 20, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 259 of the GALT protein (p.Arg259Trp). This variant is present in population databases (rs786204763, gnomAD 0.003%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with galactose-1-phosphate uridyltransferase deficiency (PMID: 8741038, 22944367, 23749220, 25268296). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 189191). 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: 11152465). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg259 amino acid residue in GALT. Other variant(s) that disrupt this residue have been observed in individuals with GALT-related conditions (PMID: 22461411), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 25, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 08, 2021 | NM_000155.3(GALT):c.775C>T(R259W) is a missense variant classified as likely pathogenic in the context of galactosemia. R259W has been observed in cases with relevant disease (PMID: 8892021, 10535394, 21779791, 22944367, 25268296, 27363831, 9396569, 31194895, 23749220). Functional assessments of this variant are available in the literature (PMID: 11152465). R259W has been observed in population frequency databases (gnomAD: AMR 0.003%). In summary, NM_000155.3(GALT):c.775C>T(R259W) 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. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 08, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 12, 2023 | Functional analysis found this variant is associated with significantly reduced GALT enzyme activity (Riehman et al., 2001); Not observed at a 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: 31194895, 11261429, 23749220, 20008339, 17041746, 31194252, 10408771, 31589614, 11152465, 8741038) - |
Galactosemia Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 29, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at