rs373979283
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000521.4(HEXB):āc.796T>Gā(p.Tyr266Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,611,290 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. Y266C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000521.4 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 |
---|---|---|---|---|---|---|---|
HEXB | NM_000521.4 | c.796T>G | p.Tyr266Asp | missense_variant | 7/14 | ENST00000261416.12 | |
HEXB | NM_001292004.2 | c.121T>G | p.Tyr41Asp | missense_variant | 7/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HEXB | ENST00000261416.12 | c.796T>G | p.Tyr266Asp | missense_variant | 7/14 | 1 | NM_000521.4 | P1 | |
HEXB | ENST00000511181.5 | c.121T>G | p.Tyr41Asp | missense_variant | 7/14 | 1 | |||
HEXB | ENST00000504459.5 | upstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152248Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251446Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135894
GnomAD4 exome AF: 0.0000356 AC: 52AN: 1459042Hom.: 0 Cov.: 29 AF XY: 0.0000372 AC XY: 27AN XY: 726064
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152248Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74382
ClinVar
Submissions by phenotype
Sandhoff disease Pathogenic:4
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Aug 31, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 14, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 28, 2021 | Variant summary: HEXB c.796T>G (p.Tyr266Asp) results in a non-conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain (IPR015883) 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 2e-05 in 251446 control chromosomes. c.796T>G has been reported in the literature as homozygous and compound heterozygous genotypes in individuals affected with Sandhoff Disease (example, Gort_2012, Mugnaini_2017, Gaignard_2013). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Gort_2012). The most pronounced variant effect results in <10% of normal total Hexosaminidase activity in serum and fibroblasts of an affected individual with a homozygous genotype. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 21, 2023 | For these reasons, this variant has been classified as Pathogenic. 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 HEXB protein function. ClinVar contains an entry for this variant (Variation ID: 381669). This missense change has been observed in individual(s) with Sandhoff disease (PMID: 17015493, 22789865, 23046579). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs373979283, gnomAD 0.005%). This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 266 of the HEXB protein (p.Tyr266Asp). - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 11, 2016 | The Y266D variant in the HEXB gene has been reported previously in association with Sandoff disease when present in the homozygous state or when in trans with another pathogenic variant (Maegawa et al., 2006; Gort et al., 2012). The Y266D variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y266D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The Y266D variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at