Submissions for variant NM_003923.3(FOXH1):c.1049A>G (p.Asp350Gly)

gnomAD frequency: 0.00045  dbSNP: rs138792321

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000557713	SCV000629757	uncertain significance	Holoprosencephaly sequence	2024-12-25	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 350 of the FOXH1 protein (p.Asp350Gly). This variant is present in population databases (rs138792321, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with holoprosencephaly and/or tetralogy of Fallot (PMID: 18538293). ClinVar contains an entry for this variant (Variation ID: 458508). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FOXH1 protein function with a negative predictive value of 80%. 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.
Illumina Laboratory Services, Illumina	RCV000557713	SCV001324996	uncertain significance	Holoprosencephaly 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001811035	SCV001472721	uncertain significance	not provided	2020-03-30	criteria provided, single submitter	clinical testing	The FOXH1 c.1049A>G; p.Asp350Gly variant (rs138792321) is reported in the literature in two individuals affected with holoprosencephaly, one of whom was homozygous for the variant, and another individual with tetralogy of Fallot (Roessler 2008). This variant is found in the general population with an overall allele frequency of 0.02% (67/274084 alleles) in the Genome Aggregation Database. The aspartate at codon 350 is weakly conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. This variant also exhibited decreased ability to rescue zebrafish morphant defects, however the extent and significance of such decreased activity is unclear. Due to limited information, the clinical significance of the p.Asp350Gly variant is uncertain at this time. References: Roessler et al., Reduced NODAL signaling strength via mutation of several pathway members including FOXH1 is linked to human heart defects and holoprosencephaly. Am J Hum Genet. 2008 Jul;83(1):18-29.
GeneDx	RCV001811035	SCV005201838	uncertain significance	not provided	2023-12-19	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20497191, 18538293)