Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000414383 | SCV000491333 | likely pathogenic | not provided | 2016-06-01 | criteria provided, single submitter | clinical testing | The A6E variant in the ASNS gene was reported previously in a French Canadian family in the compound heterozygous state with the R550C variant in three siblings with progressive microcephaly, infantile epilepsy, profound developmental delay, axial hypotonia, and an abnormal brain MRI (Ruzzo et al., 2013). The A6E variant was not observed in approximately 6500 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 A6E variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. The A6E variant was reported to impair ASNS gene function by reducing protein expression in HEK and COS cells (Ruzzo et al., 2013). The A6E variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. |
| Labcorp Genetics |
RCV000414383 | SCV001386694 | pathogenic | not provided | 2024-02-02 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 6 of the ASNS protein (p.Ala6Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with asparagine synthetase deficiency (PMID: 24139043). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 91842). 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 ASNS protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ASNS function (PMID: 24139043). For these reasons, this variant has been classified as Pathogenic. |
| OMIM | RCV000077750 | SCV000109556 | pathogenic | Congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome | 2013-10-16 | no assertion criteria provided | literature only |