Submissions for variant NM_003865.3(HESX1):c.385G>A (p.Val129Ile)

gnomAD frequency: 0.00064  dbSNP: rs143057250

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000584901	SCV000693109	uncertain significance	not provided	2017-12-01	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000584901	SCV000705401	uncertain significance	not provided	2017-02-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000258196	SCV000897137	uncertain significance	Septo-optic dysplasia sequence	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000258196	SCV001308257	likely benign	Septo-optic dysplasia sequence	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001317207	SCV001507856	uncertain significance	Septo-optic dysplasia sequence; GROWTH HORMONE DEFICIENCY WITH PITUITARY ANOMALIES	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 129 of the HESX1 protein (p.Val129Ile). This variant is present in population databases (rs143057250, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with HESX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 267733). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Hehr Laboratory, Center for Human Genetics Regensburg	RCV000258196	SCV000328442	uncertain significance	Septo-optic dysplasia sequence	2016-09-05	no assertion criteria provided	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000258196	SCV000692279	uncertain significance	Septo-optic dysplasia sequence	2009-04-28	no assertion criteria provided	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000583982	SCV000692280	uncertain significance	Pituitary hormone deficiency, combined, 1	2009-04-28	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000584901	SCV001797309	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000584901	SCV001925235	likely benign	not provided		no assertion criteria provided	clinical testing
Yale Center for Mendelian Genomics, Yale University	RCV001849354	SCV002106760	uncertain significance	Amenorrhea	2021-03-08	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003947822	SCV004774007	likely benign	HESX1-related disorder	2022-05-12	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).