Submissions for variant NM_020631.6(PLEKHG5):c.971T>C (p.Ile324Thr)

gnomAD frequency: 0.00012  dbSNP: rs746862312

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000222151	SCV000279989	uncertain significance	not provided	2016-10-19	criteria provided, single submitter	clinical testing	The I324T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 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 I324T 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. This substitution occurs at a position that is conserved in mammals; however, Threonine is observed at this position in evolution. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000797810	SCV000937391	uncertain significance	Neuronopathy, distal hereditary motor, autosomal recessive 4; Charcot-Marie-Tooth disease recessive intermediate C	2022-09-19	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 324 of the PLEKHG5 protein (p.Ile324Thr). This variant is present in population databases (rs746862312, gnomAD 0.03%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with PLEKHG5-related conditions. ClinVar contains an entry for this variant (Variation ID: 234903). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000222151	SCV001713776	uncertain significance	not provided	2019-04-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002381755	SCV002695287	uncertain significance	Inborn genetic diseases	2020-12-02	criteria provided, single submitter	clinical testing	The p.I324T variant (also known as c.971T>C), located in coding exon 8 of the PLEKHG5 gene, results from a T to C substitution at nucleotide position 971. The isoleucine at codon 324 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and threonine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.