Submissions for variant NM_003865.3(HESX1):c.509C>T (p.Ser170Leu)

gnomAD frequency: 0.00001  dbSNP: rs28936703

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000729620	SCV000857295	uncertain significance	not provided	2017-10-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002512890	SCV003265872	uncertain significance	Septo-optic dysplasia sequence; GROWTH HORMONE DEFICIENCY WITH PITUITARY ANOMALIES	2023-08-17	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: 11136712, 11748154). 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: 7692). This missense change has been observed in individual(s) with clinical features of autosomal dominant septo-optic dysplasia (PMID: 11136712, 11748154, 17148560, 34906519). This variant is present in population databases (rs28936703, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 170 of the HESX1 protein (p.Ser170Leu).
University of Washington Department of Laboratory Medicine, University of Washington	RCV005255553	SCV005908136	uncertain significance	Septo-optic dysplasia sequence	2023-10-10	criteria provided, single submitter	clinical testing	The p.Ser170Leu variant in the HESX1 gene has been previously reported in multiple unrelated individuals with clinical features of autosomal dominant HESX1-related disorders, including isolated growth hormone deficiency (Parks 1999, Brickman 2001, Thomas 2001). The p.Ser170Leu variant has been submitted to ClinVar (Variation ID: 7692, ncbi.nlm.nih.gov/clinvar/), and has been identified in 9/251076 (v4.0.0: 98/1613136) chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This allele frequency is low enough to be consistent with a milder hypomorphic allele. In silico tools predict that the p.Ser170Leu variant is deleterious. Functional studies of this variant are supportive of a deleterious effect to the protein; however, it is unclear if this would be sufficient to be disease-causing (Brickman 2001, Thomas 2001). Using ACMG guidelines, this variant was classified as a variant of uncertain significance (ACMG evidence codes used: PS3_moderate, PS4_supporting).
OMIM	RCV000008131	SCV000028336	pathogenic	SEPTOOPTIC DYSPLASIA, MILD	2001-01-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004752692	SCV005351207	likely pathogenic	HESX1-related disorder	2024-03-14	no assertion criteria provided	clinical testing	The HESX1 c.509C>T variant is predicted to result in the amino acid substitution p.Ser170Leu. This variant was reported in multiple heterozygous individuals with isolated growth hormone deficiency, one of whom also had optic hypoplasia (Parks et al 1999. PubMed ID: 10599689; Brickman et al. 2001. PubMed ID: 11748154). This variant was also reported in a heterozygous individual with ventriculomegaly, partial agenesis of the corpus collosum, cavum septum pellucidum, adrenal gland agenesis, aplasia/hypoplasia of the optic tract, and optic nerve aplasia (Marangoni et al. 2021. PubMed ID: 34906519). Results of DNA binding assays suggest the p.Ser170Leu variant in heterozygous individuals is functionally compromised (Thomas et al. 2001. PubMed ID: 11136712; Brickman et al. 2001. PubMed ID: 11748154). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic.