NM_006214.4:c.823C>T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_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 (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000081 ( 0 hom. )

Consequence

PHYH
NM_006214.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 2.28

Variant links:

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]

PHYH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 rank	MANE	Protein	UniProt
PHYH	NM_006214.4 link	c.823C>T	p.Arg275Trp	missense_variant	Exon 7 of 9	ENST00000263038.9	NP_006205.1	O14832-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PHYH	ENST00000263038.9 link	c.823C>T	p.Arg275Trp	missense_variant	Exon 7 of 9	1	NM_006214.4	ENSP00000263038.4	O14832-1
PHYH	ENST00000396920.7 link	c.772C>T	p.Arg258Trp	missense_variant	Exon 7 of 9	5		ENSP00000380126.3	B1ALH6
PHYH	ENST00000396913.6 link	c.523C>T	p.Arg175Trp	missense_variant	Exon 6 of 8	5		ENSP00000380121.2	O14832-2
PHYH	ENST00000453759.6 link	c.523C>T	p.Arg175Trp	missense_variant	Exon 7 of 7	5		ENSP00000412525.2	C9IYS5

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152052

Hom.:

Cov.:

show subpopulations

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:

AN:

251484

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

135918

show subpopulations

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.:

Cov.:

AF XY:

0.0000770

AC XY:

AN XY:

727230

show subpopulations

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:

AN:

152052

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74260

show subpopulations

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.:

Bravo

AF:

0.000136

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Phytanic acid storage disease

Pathogenic:6

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 22, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

May 12, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). -

not provided

Pathogenic:4

Apr 22, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Jul 17, 2018

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). -

Mar 01, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4_moderate, PM3, PM5, PP3, PP6 -

Retinitis pigmentosa

Pathogenic:2

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Apr 01, 2021

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Inborn genetic diseases

Pathogenic:1

Dec 15, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

REFSUM DISEASE, ADULT, 1

Pathogenic:1

May 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.54

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

.;D;.;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.73

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

.;M;.;.

PrimateAI

Uncertain

0.55

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over