Submissions for variant NM_006214.4(PHYH):c.354C>G (p.Ile118Met)

gnomAD frequency: 0.00006  dbSNP: rs779724199

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494522	SCV000581755	uncertain significance	not provided	2017-02-06	criteria provided, single submitter	clinical testing	The I118M variant in the PHYH gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The I118M variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The I118M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret I118M as a variant of uncertain significance.
Illumina Laboratory Services, Illumina	RCV001107607	SCV001264773	uncertain significance	Phytanic acid storage disease	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000494522	SCV002314798	uncertain significance	not provided	2021-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with methionine at codon 118 of the PHYH protein (p.Ile118Met). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs779724199, ExAC 0.001%). This variant has not been reported in the literature in individuals affected with PHYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 429240). 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.