Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000003708 | SCV000916031 | uncertain significance | Deficiency of hyaluronoglucosaminidase | 2018-10-15 | criteria provided, single submitter | clinical testing | The HYAL1 c.802G>A (p.Glu268Lys) variant is a missense variant that has been reported in one study in which it is found in a compound heterozygous state with a stop-gained variant in one individual with mucopolysaccharidosis IX (Triggs-Raine et al., 1999; Natowicz et al., 1996). The patient's unaffected father and paternal grandmother both carried the variant in a heterozygous state. The variant was not found in 100 control alleles and is reported at a frequency of 0.000256 in the European (non-Finnish) population of the Exome Aggregation Consortium. The patient had deficient serum hyaluronidase activity and 38- to 90-fold elevated concentration of serum hyaluronic acid (Natowicz et al., 1996). Triggs-Raine et al. (1999) predict the variant to disrupt HYAL1 activity because of the difference in charges between the glutamine and lysine residues. The Glu268 residue is highly conserved and is likely critical for the function of an active site in the HYAL1 protein. In silico analysis of native and mutant HYAL demonstrated differences in folding pattern, secondary structure elements, dihedral angles, and binding strength (Paul & Rajasekaran 2017). The evidence for this variant is limited. The p.Glu268Lys variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for mucopolysaccharidosis, type IX. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Labcorp Genetics |
RCV000003708 | SCV002168546 | uncertain significance | Deficiency of hyaluronoglucosaminidase | 2021-10-24 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 268 of the HYAL1 protein (p.Glu268Lys). This variant is present in population databases (rs104893743, gnomAD 0.02%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IX (PMID: 10339581). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3530). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| OMIM | RCV000003708 | SCV000023871 | pathogenic | Deficiency of hyaluronoglucosaminidase | 1999-05-25 | no assertion criteria provided | literature only |