ClinVar Miner

Submissions for variant NM_006080.3(SEMA3A):c.2198G>A (p.Arg733His)

gnomAD frequency: 0.00004  dbSNP: rs318240753
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, University of Leipzig Medical Center 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.
PreventionGenetics, part of Exact Sciences 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.
UniProtKB/Swiss-Prot RCV000059792 SCV000091362 not provided not provided no assertion provided not provided

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