rs61742258
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000512.5(GALNS):c.775C>T(p.Arg259Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,613,554 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 Conflicting classifications of pathogenicity (no stars). 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_000512.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GALNS | NM_000512.5 | c.775C>T | p.Arg259Trp | missense_variant | 8/14 | ENST00000268695.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GALNS | ENST00000268695.10 | c.775C>T | p.Arg259Trp | missense_variant | 8/14 | 1 | NM_000512.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152158Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000799 AC: 2AN: 250168Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135218
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461396Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4AN XY: 726912
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152158Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74318
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2022 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 16, 2024 | Variant summary: GALNS c.775C>T (p.Arg259Trp) results in a non-conservative amino acid change located in the Sulfatase, N-terminal (IPR000917) 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 8e-06 in 250168 control chromosomes. c.775C>T has been reported in the literature in at-least three unrelated individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A), in each case, this variant was seen along with a different apparently pathogenic variant (example, Lv_2021, Moosa_2022, Yi_2022). 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. The following publications have been ascertained in the context of this evaluation (PMID: 34557487, 35616356, 35212421). ClinVar contains an entry for this variant (Variation ID: 1675645). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at