Submissions for variant NM_178138.6(LHX3):c.920G>C (p.Arg307Pro)

gnomAD frequency: 0.00073  dbSNP: rs182345541

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000302742	SCV000329398	uncertain significance	not provided	2016-07-20	criteria provided, single submitter	clinical testing	The R312P variant in the LHX3 gene has been reported previously in one individual with pituitary aplasia; however, no second LHX3 variant was identified, and R312P was also present in the heterozygous state in this individual's unaffected father and sister (Sobrier et al., 2006). The R312P variant was not observed at any significant frequency in approximately 6300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R312P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. We interpret R312P as a variant of uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000766051	SCV000897507	uncertain significance	Non-acquired combined pituitary hormone deficiency with spine abnormalities	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000766051	SCV001330950	likely benign	Non-acquired combined pituitary hormone deficiency with spine abnormalities	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.
Invitae	RCV000302742	SCV003247158	uncertain significance	not provided	2022-03-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 312 of the LHX3 protein (p.Arg312Pro). This variant is present in population databases (rs182345541, gnomAD 0.1%), 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 LHX3-related conditions. ClinVar contains an entry for this variant (Variation ID: 279837). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). 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.
Natera, Inc.	RCV001273808	SCV001457320	uncertain significance	Combined pituitary hormone deficiencies, genetic form	2019-12-24	no assertion criteria provided	clinical testing