Submissions for variant NM_004807.3(HS6ST1):c.1144C>T (p.Arg382Trp)

gnomAD frequency: 0.00101  dbSNP: rs199538589

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455725	SCV000539314	benign	not specified	2016-03-29	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, unrelated to patient disease
Mendelics	RCV000156968	SCV001135948	benign	Hypogonadotropic hypogonadism 7 with or without anosmia	2023-08-22	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001258243	SCV001435156	benign	Hypogonadotropic hypogonadism 15 with or without anosmia		criteria provided, single submitter	research	The heterozygous p.Arg382Trp variant in HS6ST1 has been identified in 6 individuals with idiopathic hypogonadotropic hypogonadism (PMID: 21700882, 23643382), and has been identified in >1% of South Asian chromosomes and 4 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Arg382Trp variant may silghtly impact protein function (PMID: 21700882). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as benign for autosomal dominant idiopathic hypogonadotropic hypogonadism.
GeneDx	RCV001358502	SCV001946188	benign	not provided	2020-03-24	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21700882, 23643382, 26207952, 27535533, 30669598)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001358502	SCV002411889	likely benign	not provided	2024-08-06	criteria provided, single submitter	clinical testing
OMIM	RCV000032891	SCV000056662	risk factor	HYPOGONADOTROPIC HYPOGONADISM 15 WITH OR WITHOUT ANOSMIA, SUSCEPTIBILITY TO	2011-07-12	no assertion criteria provided	literature only
Chan Lab, Boston Children's Hospital	RCV000156968	SCV000206689	likely pathogenic	Hypogonadotropic hypogonadism 7 with or without anosmia	2014-11-01	flagged submission	case-control
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358502	SCV001554255	uncertain significance	not provided		flagged submission	clinical testing	The HS6ST1 p.R382W variant was identified in 5 of 1590 proband chromosomes (frequency: 0.00314) from individuals or families with idiopathic hypogonadotropic hypogonadism (Zhu_2015_PMID:25636053, Miraoui_2013_PMID:23643382, Tornberg_2011_PMID:21700882). The variant was identified in dbSNP (ID: rs199538589) and in ClinVar (classified as likely pathogenic by the Chan Lab at Boston Children's Hospital and benign by Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine with the associated condition of hypogonadotrophic hypogonadism). The variant was also identified in control databases in 480 of 278216 chromosomes (3 homozygous) at a frequency of 0.001725 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 337 of 30560 chromosomes (freq: 0.01103), Ashkenazi Jewish in 35 of 10268 chromosomes (freq: 0.003409), Latino in 31 of 35288 chromosomes (freq: 0.000879), African in 16 of 23958 chromosomes (freq: 0.000668), European (non-Finnish) in 56 of 126664 chromosomes (freq: 0.000442), Other in 3 of 7078 chromosomes (freq: 0.000424) and East Asian in 2 of 19480 chromosomes (freq: 0.000103), but was not observed in the European (Finnish) population. The p.Arg382 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In vitro functional analysis demonstrated a 25 to 35% reduction in enzymatic activity with the p.R382W mutant compared to wildtype, and in an in vivo assay involving C. elegans, the p.R382W mutant displayed a reduced capacity to rescue a kal1-dependent axon branching phenotype compared to wildtype HS6ST1 (Tornberg_2011_PMID:21700882). Tornberg et al. (2011) identified the p.R382W variant in three unrelated individuals with hypogonadotropic hypogonadism: a female and two males (1 with anosmia and 2 with a normal sense of smell). The female proband had a brother with delayed puberty who did not carry the HS6ST1 p.R382W mutation, whereas the anosmic male proband had an unaffected brother who did carry the mutation, indicating that the variant did not segregate with disease (Tornberg_2011_PMID:21700882). In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
PreventionGenetics, part of Exact Sciences	RCV003917537	SCV004738842	uncertain significance	HS6ST1-related disorder	2023-12-20	no assertion criteria provided	clinical testing	The HS6ST1 c.1144C>T variant is predicted to result in the amino acid substitution p.Arg382Trp. This variant has been reported in multiple unrelated patients with hypogonadotropic hypogonadism (referred to as R372W in Tornberg et al. 2011. PubMed ID: 21700882; Miraoui et al. 2013. PubMed ID: 23643382; Zhu et al. 2015. PubMed ID: 25636053), and was defined as a founder allele in Caucasian and South Asian ethnicities (Choi et al. 2015. PubMed ID: 26207952, Table 2). In vitro and in vivo functional studies showed that the p.Arg382Trp variant resulted in reduced enzymatic activity compared to wild-type (referred to as R372W in Tornberg et al. 2011. PubMed ID: 21700882). However, this variant is found at an allele frequency of up to ~1.12% in South Asian individuals (including 3 homozygotes) in a large population database of individuals with unknown phenotype, which is likely too common to be a primary cause of autosomal dominant disease. Of note, in a recent publication, this variant was found in a patient with milder adult-onset form of hypogonadotropic hypogonadism (Cangiano et al. 2019. PubMed ID: 30669598, Table S1). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.