ClinVar Miner

Submissions for variant NM_004807.3(HS6ST1):c.917G>A (p.Arg306Gln)

gnomAD frequency: 0.00081  dbSNP: rs201307896
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001852660 SCV002199645 uncertain significance not provided 2021-06-25 criteria provided, single submitter clinical testing This variant has been observed in individual(s) with Kallmann syndrome and hypogonadotrophic hypogonadism (PMID: 21700882, 25077900). This variant is present in population databases (rs201307896, ExAC 0.1%). This sequence change replaces arginine with glutamine at codon 306 of the HS6ST1 protein (p.Arg306Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this variant affects HS6ST1 protein function (PMID: 21700882). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant is also known as R296Q.
Mendelics RCV002247411 SCV002517193 uncertain significance not specified 2022-05-04 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001852660 SCV004011192 uncertain significance not provided 2023-05-01 criteria provided, single submitter clinical testing HS6ST1: PS4:Moderate, PM5:Supporting, PP3
PreventionGenetics, part of Exact Sciences RCV003952386 SCV004772081 uncertain significance HS6ST1-related disorder 2024-01-08 criteria provided, single submitter clinical testing The HS6ST1 c.917G>A variant is predicted to result in the amino acid substitution p.Arg306Gln. This variant has been reported in the heterozygous state in several unrelated individuals with hypogonadotropic hypogonadism (referred to as R296Q in Tornberg et al. 2011. PubMed ID: 21700882; Miraoui et al. 2013. PubMed ID: 23643382, Table S3; Marcos et al. 2014. PubMed ID: 25077900, Supplementary table 2). In vitro functional studies showed that the p.Arg306Gln variant displayed some reduced enzymatic activity (70-80% of WT activity) (referred to as R296Q in Tornberg et al. 2011. PubMed ID: 21700882). However, this variant is reported in 0.12% of alleles in individuals of European (Non-Finnish)descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Breakthrough Genomics, Breakthrough Genomics RCV001852660 SCV005187904 uncertain significance not provided criteria provided, single submitter not provided
OMIM RCV000032893 SCV000056664 risk factor Hypogonadotropic hypogonadism 15 with anosmia 2011-07-12 no assertion criteria provided literature only

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