ClinVar Miner

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

gnomAD frequency: 0.00007  dbSNP: rs104894178
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Total submissions: 14
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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
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000665657 SCV004809515 likely pathogenic Phytanic acid storage disease 2024-04-04 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000665657 SCV004848927 likely pathogenic Phytanic acid storage disease 2023-02-02 criteria provided, single submitter clinical testing The p.Arg275Trp variant in PHYH has been reported in 3 homozygous and 2 compound heterozygous individuals with Refsum disease and 1 compound heterozygote with retinitis pigmentosa (Mihalik 1997 PMID: 9326939, Chahal 1998 PMID: 9657395, Jansen 2000 PMID: 10767344, Carss 2017 PMID: 28041643). It has also been identified in 0.28% (10/3472) Ashkenazi Jewish and 0.001% (1/68022) European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 7580). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro/in vivo functional studies provide some evidence that this variant causes the protein to be enzymatically inactive (Mihalik 1997 PMID: 9326939, Mukherji 2001 PMID: 11555634); however, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Refsum disease. ACMG/AMP Criteria applied: PM3_Strong, PS3_Moderate, PM2_Supporting, PP3.
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

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