Submissions for variant NM_003865.3(HESX1):c.541A>G (p.Thr181Ala)

gnomAD frequency: 0.00008  dbSNP: rs28936704

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000592959	SCV000702349	uncertain significance	not provided	2016-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001147431	SCV001308255	uncertain significance	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV000592959	SCV001986172	uncertain significance	not provided	2021-04-09	criteria provided, single submitter	clinical testing	Identified as heterozygous in a patient with isolated growth hormone deficiency and pituitary hypoplasia and in a patient with combined pituitary hormone deficiency, anterior pituitary hypoplasia, and ectopic posterior lobe in published literature (Thomas et al., 2001; Jullien et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11136712, 33098107)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851729	SCV002113127	uncertain significance	Septo-optic dysplasia sequence; GROWTH HORMONE DEFICIENCY WITH PITUITARY ANOMALIES	2023-11-15	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 181 of the HESX1 protein (p.Thr181Ala). This variant is present in population databases (rs28936704, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of HESX1-related conditions (PMID: 11136712, 32483926, 33098107). ClinVar contains an entry for this variant (Variation ID: 7693). 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 alanine 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.
Ambry Genetics	RCV002512891	SCV003749865	uncertain significance	Inborn genetic diseases	2022-04-11	criteria provided, single submitter	clinical testing	The c.541A>G (p.T181A) alteration is located in exon 4 (coding exon 4) of the HESX1 gene. This alteration results from a A to G substitution at nucleotide position 541, causing the threonine (T) at amino acid position 181 to be replaced by an alanine (A). (Thomas, 2001) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000592959	SCV004150363	likely benign	not provided	2023-01-01	criteria provided, single submitter	clinical testing	HESX1: BP4
OMIM	RCV000008132	SCV000028337	pathogenic	GROWTH HORMONE DEFICIENCY WITH PITUITARY ANOMALIES	2001-01-01	no assertion criteria provided	literature only