Submissions for variant NM_003865.3(HESX1):c.475C>T (p.Arg159Trp)

gnomAD frequency: 0.00004  dbSNP: rs770886420

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001574554	SCV001801396	likely pathogenic	not provided	2025-04-08	criteria provided, single submitter	clinical testing	Published functional studies demonstrate the p.R159W variant disrupts normal protein function (PMID: 27000987, 28396770); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28396770, 31395954, 27000987)
Fulgent Genetics, Fulgent Genetics	RCV002506683	SCV002816369	likely pathogenic	Septo-optic dysplasia sequence	2021-12-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002573229	SCV003311161	uncertain significance	Septo-optic dysplasia sequence; GROWTH HORMONE DEFICIENCY WITH PITUITARY ANOMALIES	2023-09-17	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this missense change affects HESX1 function (PMID: 27000987, 28396770). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1206790). This missense change has been observed in individual(s) with clinical features of septo-optic dysplasia (PMID: 2700987, 28396770, 31395954). This variant is present in population databases (rs770886420, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 159 of the HESX1 protein (p.Arg159Trp).
Revvity Omics, Revvity	RCV002506683	SCV003810783	uncertain significance	Septo-optic dysplasia sequence	2021-09-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004801040	SCV005422249	likely pathogenic	HESX1-Related Disorders	2024-10-14	criteria provided, single submitter	clinical testing	Variant summary: HESX1 c.475C>T (p.Arg159Trp) results in a non-conservative amino acid change located in the Homeodomain (Homeodomain) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250890 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.475C>T has been reported in the literature in at least one compound heterozygous individual affected with Combined Pituitary Hormone Deficiency and pituitary aplasia (e.g., Fang_2016). The variant has also been reported in a heterozygous individual with Septooptic dysplasia, however a second HESX1 variant was not described and segregation of the variant with disease was not demonstrated (e.g., Wojcik_2019, Pozzi_2017). At least two publications report experimental evidence evaluating an impact on protein function, demonstrating that the variant results in altered localization, reduced protein expresssion, and altered or abolished repressor activity, possibly due to altered DNA binding abilities (e.g., Fang_2016, Pozzi_2017). The following publications have been ascertained in the context of this evaluation (PMID: 27000987, 28396770, 31395954). ClinVar contains an entry for this variant (Variation ID: 1206790). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV002506683	SCV004174111	likely pathogenic	Septo-optic dysplasia sequence		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004753369	SCV005361103	likely pathogenic	HESX1-related disorder	2024-09-05	no assertion criteria provided	clinical testing	The HESX1 c.475C>T variant is predicted to result in the amino acid substitution p.Arg159Trp. The variant c.475C>T has been identified in the compound heterozygous state in a patient with pituitary aplasia (PA) and combined pituitary hormone deficiency (CPHD, Fang et al. 2016. PMID: 27000987). Additionally, this particular variant has been reported in the heterozygous state in a patient with septo-optic dysplasia (SOD) and his mother who is asymptomatic despite carrying the same variant, suggesting reduced penetrance of this variant (Pozzi et al. 2017. PMID: 28396770; Supplementary Table 3c, Wojcik et al. 2019. PubMed ID: 31395954). Functional analysis in this study showed that the p.Arg159Trp substitution may reduce the expression of HESX1 protein and impair its DNA binding properties (Pozzi et al. 2017. PMID: 28396770). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.