Submissions for variant NM_006214.4(PHYH):c.823C>T (p.Arg275Trp)

gnomAD frequency: 0.00007  dbSNP: rs104894178

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255609	SCV000322353	pathogenic	not provided	2021-04-22	criteria provided, single submitter	clinical testing	Functional studies have shown R275W results in impaired 2-oxoglutarate binding and loss of enzyme activity (Mihalik et al.,1997; Mukherji et al., 2001); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9326939, 31980526, 32581362, 11555634, 28041643, 10767344, 14974078, 31589614)
Counsyl	RCV000665657	SCV000789813	likely pathogenic	Phytanic acid storage disease	2017-05-12	criteria provided, single submitter	clinical testing
Invitae	RCV000255609	SCV001211881	pathogenic	not provided	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 275 of the PHYH protein (p.Arg275Trp). This variant is present in population databases (rs104894178, gnomAD 0.4%). This missense change has been observed in individual(s) with autosomal recessive Refsum disease (PMID: 9657395, 10767344, 28041643). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 7580). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PHYH protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PHYH function (PMID: 1155634, 9326939). For these reasons, this variant has been classified as Pathogenic.
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000665657	SCV001251454	pathogenic	Phytanic acid storage disease		criteria provided, single submitter	research	The pathogenic PHYH (p.R275W) variant has been reported previously in individuals with Refsum disease in the homozygous state and the compound heterozygous state (PMID: 9326939; 10767344).
Mayo Clinic Laboratories, Mayo Clinic	RCV000255609	SCV001713531	pathogenic	not provided	2021-03-01	criteria provided, single submitter	clinical testing	PS3, PS4_moderate, PM3, PM5, PP3, PP6
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000505105	SCV001950327	pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Arg275Trp variant in PHYH was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PM1, PS3, PM3. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Genetic Services Laboratory, University of Chicago	RCV000255609	SCV002064487	likely pathogenic	not provided	2018-07-17	criteria provided, single submitter	clinical testing	DNA sequence analysis of the PHYH gene demonstrated a sequence change, c.823C>T, in exon 7 that results in an amino acid change, p.Arg275Trp. The p.Arg275Trp change affects a highly conserved amino acid residue located in a domain of the PHYH protein that is known to be functional. The p.Arg275Trp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This particular amino acid change has been described in the literature in the homozygous state in patients with Refsum disease (Mihalik et. al., 1997; Chahal et al, 1998). Functional studies demonstrate that this variant is enzymatically inactive (Mihalik et. al., 1997; Chahal et al, 1998). This sequence change has been described in the EXAC database with a low population frequency of 0.015% (dbSNP rs104894178).
Ambry Genetics	RCV002426496	SCV002681849	pathogenic	Inborn genetic diseases	2017-12-15	criteria provided, single submitter	clinical testing	The p.R275W pathogenic mutation (also known as c.823C>T), located in coding exon 7 of the PHYH gene, results from a C to T substitution at nucleotide position 823. The arginine at codon 275 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been detected in homozygous states in individuals with Refsum disease (Jansen GA et al. Hum. Mol. Genet., 2000 May;9:1195-200; Mukherji M et al. Hum. Mol. Genet., 2001 Sep;10:1971-82). This alteration was also described in heterozygous state in an individual with retinitis pigmentosa, who also carried PHYH c.678+5G>T; however, the phase is unclear (Carss KJ et al. Am. J. Hum. Genet., 2017 01;100:75-90). This alteration has been shown to abolish the enzyme activity (Jansen GA et al. Hum. Mol. Genet., 2000 May;9:1195-200; Mukherji M et al. Hum. Mol. Genet., 2001 Sep;10:1971-82; Mihalik SJ et al. Nat. Genet., 1997 Oct;17:185-9). In addition, an alteration changing the same amino acid residue, R275Q, has also been reported in homozygous state in an RD patient, and shown to abolish enzyme activity (Jansen GA et al. Hum. Mol. Genet., 2000 May;9:1195-200; Mukherji M et al. Hum. Mol. Genet., 2001 Sep;10:1971-82). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV000665657	SCV002809954	likely pathogenic	Phytanic acid storage disease	2022-01-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000665657	SCV004204003	pathogenic	Phytanic acid storage disease	2023-10-28	criteria provided, single submitter	clinical testing
OMIM	RCV000008018	SCV000028223	pathogenic	Refsum disease, adult, 1	2000-05-01	no assertion criteria provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000505105	SCV000598731	likely pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research