rs111033742
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000155.4(GALT):βc.652delβ(p.Leu218Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. L218L) has been classified as Benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000155.4 frameshift
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.652del | p.Leu218Ter | frameshift_variant | 7/11 | ENST00000378842.8 | |
GALT | NM_001258332.2 | c.325del | p.Leu109Ter | frameshift_variant | 5/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GALT | ENST00000378842.8 | c.652del | p.Leu218Ter | frameshift_variant | 7/11 | 1 | NM_000155.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461872Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727242
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 12, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 21, 2021 | Variant summary: GALT c.652delC (p.Leu218X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (example: c.790_792delinsTAG p.Leu264X; c.888C>G p.Tyr296X). The variant was absent in 251466 control chromosomes (gnomAD). c.652delC has been reported in the literature in a sample tested for Galactosemia confirmatory testing along with p.L218L variant. Reduced enzymatic activity was also detected in this patient (Calderon_2007). One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 02, 2023 | This sequence change creates a premature translational stop signal (p.Leu218*) in the GALT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GALT are known to be pathogenic (PMID: 22944367). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with GALT-related conditions (PMID: 17876724). ClinVar contains an entry for this variant (Variation ID: 25237). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Galactosemia Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 30, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at