Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Institute of Human Genetics, |
RCV001262880 | SCV001440915 | uncertain significance | Hypogonadotropic hypogonadism 16 with or without anosmia | 2019-01-01 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000059792 | SCV002215631 | uncertain significance | not provided | 2021-11-05 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 733 of the SEMA3A protein (p.Arg733His). This variant is present in population databases (rs318240753, gnomAD 0.006%). This missense change has been observed in individual(s) with Kallmann syndrome (PMID: 22927827). ClinVar contains an entry for this variant (Variation ID: 68835). 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"). Experimental studies have shown that this missense change affects SEMA3A function (PMID: 22927827). 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. |
Prevention |
RCV003415832 | SCV004116265 | uncertain significance | SEMA3A-related condition | 2023-12-31 | criteria provided, single submitter | clinical testing | The SEMA3A c.2198G>A variant is predicted to result in the amino acid substitution p.Arg733His. This variant was reported in an individual with Kallmann syndrome and functional studies supported an effect on the protein (Hanchate et al. 2012. PubMed ID: 22927827). This variant has also been reported in an individual with growth hormone deficiency, hypogonadotrophic hypogonadism, and borderline intellectual disability; however, they also had a pathogenic variant in SOX3 (Li et al. 2022. PubMed ID: 35295983). An alternate missense change at the same amino acid position and one at the adjacent residue have also been reported in at least one affected individual each (p.Arg733Cys, p.Arg734Gln; Human Gene Mutation Database). However, all of these variants are also documented in the gnomAD database in 4-17 heterozygous individuals, an overall frequency higher than expected for pathogenic variants in this gene (https://gnomad.broadinstitute.org/region/7-83590785-83590825). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-83590805-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |
Uni |
RCV000059792 | SCV000091362 | not provided | not provided | no assertion provided | not provided |