Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Fulgent Genetics, |
RCV002493818 | SCV002778547 | uncertain significance | Hermansky-Pudlak syndrome 3 | 2022-04-26 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001355166 | SCV003263415 | uncertain significance | not provided | 2022-07-11 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 53 of the HPS3 protein (p.Gln53His). This variant is present in population databases (rs774480483, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with HPS3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1049263). 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: "Tolerated"; 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. |
| Ambry Genetics | RCV004988583 | SCV005597987 | uncertain significance | Inborn genetic diseases | 2024-08-15 | criteria provided, single submitter | clinical testing | The c.159G>T (p.Q53H) alteration is located in exon 1 (coding exon 1) of the HPS3 gene. This alteration results from a G to T substitution at nucleotide position 159, causing the glutamine (Q) at amino acid position 53 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| Department of Pathology and Laboratory Medicine, |
RCV001355166 | SCV001549962 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The HPS3 p.Gln53His variant was not identified in the literature nor was it identified in ClinVar, Cosmic, or LOVD 3.0, The variant was identified in dbSNP (ID: rs774480483). The variant was identified in control databases in 14 of 232000 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 13 of 32198 chromosomes (freq: 0.000404), Other in 1 of 6304 chromosomes (freq: 0.000159), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), and South Asian populations. The p.Gln53 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (NNSPLICE) predict a greater than 10% difference in splicing (decrease in 5’ splicing activity five bp downstream from the variant location, not at a canonical splice site); this is not very predictive of 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. | |
| Prevention |
RCV004746340 | SCV005347546 | uncertain significance | HPS3-related disorder | 2024-09-08 | no assertion criteria provided | clinical testing | The HPS3 c.159G>T variant is predicted to result in the amino acid substitution p.Gln53His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.040% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |