Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001044039 | SCV001207813 | uncertain significance | Tay-Sachs disease | 2021-08-28 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine with valine at codon 422 of the HEXA protein (p.Leu422Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs774562271, ExAC 0.02%). This variant has not been reported in the literature in individuals affected with HEXA-related conditions. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. |
| ARUP Laboratories, |
RCV001356326 | SCV002050255 | uncertain significance | not provided | 2021-10-12 | criteria provided, single submitter | clinical testing | The HEXA c.1264C>G; p.Leu422Val variant (rs774562271), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 841751). This variant is found in the Latino population with an overall allele frequency of 0.01% (4/34592 alleles) in the Genome Aggregation Database. The leucine at codon 422 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.845). Additionally, computational analyses of splicing (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic donor splice site, although RNA studies would be required to confirm this. Given the lack of clinical and functional data, the significance of the p.Leu422Val variant is uncertain at this time. |
| Department of Pathology and Laboratory Medicine, |
RCV001356326 | SCV001551461 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The HEXA p.Leu422Val variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs774562271) and in control databases in 4 of 251460 chromosomes at a frequency of 0.00001591 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the Latino population in 4 of 34592 chromosomes (freq: 0.000116), but was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Other, or South Asian populations. The p.Leu422 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this has not been confirmed by RNA analysis and is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. | |
| Natera, |
RCV001044039 | SCV002085673 | uncertain significance | Tay-Sachs disease | 2019-02-27 | no assertion criteria provided | clinical testing |