rs104894178

chr10-13283695-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

The NM_006214.4(PHYH):c.823C>T(p.Arg275Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000805 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R275Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000081 (0 hom.)
• Consequence: PHYH NM_006214.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 2.28

Genes affected

PHYH (HGNC:8940): (phytanoyl-CoA 2-hydroxylase) This gene is a member of the PhyH family and encodes a peroxisomal protein that is involved in the alpha-oxidation of 3-methyl branched fatty acids. Specifically, this protein converts phytanoyl-CoA to 2-hydroxyphytanoyl-CoA. Mutations in this gene have been associated with Refsum disease (RD) and deficient protein activity has been associated with Zellweger syndrome and rhizomelic chondrodysplasia punctata. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_006214.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-13283694-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 10-13283695-G-A is Pathogenic according to our data. Variant chr10-13283695-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-13283695-G-A is described in Lovd as [Pathogenic]. Variant chr10-13283695-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHYH	NM_006214.4	c.823C>T	p.Arg275Trp	missense_variant	7/9	ENST00000263038.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHYH	ENST00000263038.9	c.823C>T	p.Arg275Trp	missense_variant	7/9	1	NM_006214.4	P1
PHYH	ENST00000396920.7	c.772C>T	p.Arg258Trp	missense_variant	7/9	5
PHYH	ENST00000396913.6	c.523C>T	p.Arg175Trp	missense_variant	6/8	5
PHYH	ENST00000453759.6	c.523C>T	p.Arg175Trp	missense_variant	7/7	5

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152052 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000187 AC: 47 AN: 251484 Hom.: 0 AF XY: 0.000184 AC XY: 25 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00357

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000814 AC: 119 AN: 1461866 Hom.: 0 Cov.: 32 AF XY: 0.0000770 AC XY: 56 AN XY: 727230

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00260

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152052 Hom.: 0 Cov.: 31 AF XY: 0.0000539 AC XY: 4 AN XY: 74260

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000226 Hom.: 0

Bravo AF: 0.000136

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Phytanic acid storage disease Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 28, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 31, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 12, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2023	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. -
Pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	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). -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2021	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 01, 2021	PS3, PS4_moderate, PM3, PM5, PP3, PP6 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 17, 2018	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). -

Retinitis pigmentosa Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Apr 01, 2021	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. -
Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2017

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. -

Refsum disease, adult, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.73	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-7.8	D;D;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.97
MVP		0.98
MPC		0.65
ClinPred		0.98	D
GERP RS		0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs104894178; hg19: chr10-13325695; COSMIC: COSV53816705; COSMIC: COSV53816705;