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

gnomAD frequency: 0.00081  dbSNP: rs201307896

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852660	SCV002199645	uncertain significance	not provided	2024-04-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 306 of the HS6ST1 protein (p.Arg306Gln). This variant is present in population databases (rs201307896, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Kallmann syndrome and hypogonadotrophic hypogonadism (PMID: 21700882, 25077900). This variant is also known as R296Q. ClinVar contains an entry for this variant (Variation ID: 39691). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HS6ST1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects HS6ST1 function (PMID: 21700882). 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.
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
Breakthrough Genomics, Breakthrough Genomics	RCV001852660	SCV005187904	uncertain significance	not provided		criteria provided, single submitter	not provided
GeneDx	RCV001852660	SCV005385493	uncertain significance	not provided	2024-04-22	criteria provided, single submitter	clinical testing	Identified in additional patients with hypogonadotropic hypogonadism in published literature (PMID: 25077900, 23643382); Published functional studies demonstrate reduced enzyme activity, however, additional studies are needed to confirm a damaging effect (PMID: 21700882); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as p.R296Q; This variant is associated with the following publications: (PMID: 23643382, 34426522, 25077900, 21700882, 35805171)
OMIM	RCV000032893	SCV000056664	risk factor	Hypogonadotropic hypogonadism 15 with anosmia	2011-07-12	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003952386	SCV004772081	uncertain significance	HS6ST1-related disorder	2024-01-08	no assertion criteria provided	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.