VCV000198539.33 - ClinVar

NM_006214.4(PHYH):c.734G>A (p.Arg245Gln)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(11)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006214.4(PHYH):c.734G>A (p.Arg245Gln)

Variation ID: 198539 Accession: VCV000198539.33

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10p13 10: 13283784 (GRCh38) [ NCBI UCSC ] 10: 13325784 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 2, 2016	Oct 20, 2024	Sep 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_006214.4:c.734G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006205.1:p.Arg245Gln	missense
NM_001037537.2:c.434G>A	NP_001032626.1:p.Arg145Gln	missense
NM_001323080.2:c.434G>A	NP_001310009.1:p.Arg145Gln	missense
NM_001323082.2:c.740G>A	NP_001310011.1:p.Arg247Gln	missense
NM_001323083.2:c.470G>A	NP_001310012.1:p.Arg157Gln	missense
NM_001323084.2:c.440G>A	NP_001310013.1:p.Arg147Gln	missense
NC_000010.11:g.13283784C>T
NC_000010.10:g.13325784C>T
NG_012862.1:g.21347G>A
	O14832:p.Arg245Gln

... more HGVS ... less HGVS

Protein change

R245Q, R145Q, R247Q, R147Q, R157Q

Other names

Canonical SPDI

NC_000010.11:13283783:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00539 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00404

1000 Genomes Project 30x 0.00453

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00454

1000 Genomes Project 0.00539

The Genome Aggregation Database (gnomAD) 0.00690

The Genome Aggregation Database (gnomAD), exomes 0.00761

Exome Aggregation Consortium (ExAC) 0.00784

Links

ClinGen: CA203488 UniProtKB: O14832#VAR_017491 dbSNP: rs62619919 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PHYH		-	-	GRCh38 GRCh37	449	511

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Benign (2)	criteria provided, multiple submitters, no conflicts	Nov 8, 2014	RCV000179914.12
Phytanic acid storage disease	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Sep 1, 2024	RCV000665931.13
Nonsyndromic cleft lip palate	no classifications from unflagged records (1)	no classifications from unflagged records	Aug 1, 2024	RCV000755125.2
not provided	Benign (3)	criteria provided, multiple submitters, no conflicts	Jul 1, 2024	RCV000950185.20
Vitamin D-dependent rickets type II with alopecia	Benign (1)	criteria provided, single submitter	-	RCV001258288.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (Nov 08, 2014)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000232234.5 First in ClinVar: Jun 28, 2015 Last updated: May 03, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PHYH http://exac.broadinstitute.org/v… http://exac.broadinstitute.org/variant/10-13325784-C-T Number of individuals with the variant: 2 Sex: mixed
Likely benign (Mar 06, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Phytanic acid storage disease Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000790142.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (3) PubMed: 10767344‚ 14974078‚ 16186124
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Vitamin D-dependent rickets type II with alopecia (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001435215.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020	Publications: PubMed (1) PubMed: 10767344 Comment: The p.Arg245Gln variant in PHYH has been identified in cis with p.Asp177Gly and in 4 individuals with Refsum disease, including 2 homozygotes and 2 heterozygotes … (more) The p.Arg245Gln variant in PHYH has been identified in cis with p.Asp177Gly and in 4 individuals with Refsum disease, including 2 homozygotes and 2 heterozygotes (PMID: 10767344), and has been identified in >2% of European (Finnish) chromosomes and 9 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Arg245Gln variant may not impact protein function (PMID: 10767344). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as benign for autosomal recessive Refsum disease. (less)
Benign (Aug 06, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000521053.6 First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 14974078, 10767344, 27229527, 27535533)
Benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001096473.5 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Benign (Sep 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Phytanic acid storage disease Affected status: yes Allele origin: inherited	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000845255.2 First in ClinVar: Nov 03, 2018 Last updated: Sep 29, 2024	Number of individuals with the variant: 1 Sex: male Geographic origin: Iran
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000311433.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (May 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Phytanic acid storage disease Affected status: yes Allele origin: germline	Molecular Genetics, Royal Melbourne Hospital Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004812635.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Comment: South Asian population allele frequency is 1.166% (rs62619919, 389/30616 alleles, 6 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.2.1, … (more) South Asian population allele frequency is 1.166% (rs62619919, 389/30616 alleles, 6 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.2.1, this variant is classified as BENIGN. Following criteria are met: BA1 (less)
Benign (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004126470.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: PHYH: BP4, BS1, BS2 Number of individuals with the variant: 3
Likely pathogenic (Mar 27, 2016)	Flagged submission flagged submission Method: research Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Nonsyndromic cleft lip palate Affected status: yes Allele origin: inherited	University of Washington Center for Mendelian Genomics, University of Washington Accession: SCV000882947.1 First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019	Publications: PubMed (1) PubMed: 27229527
Uncertain significance (Apr 27, 2017)	Flagged submission flagged submission (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Phytanic acid storage disease Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001264065.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (1) PubMed: 10767344 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
click to load more click to collapse
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

The p.Arg245Gln variant in PHYH has been identified in cis with p.Asp177Gly and in 4 individuals with Refsum disease, including 2 homozygotes and 2 heterozygotes (PMID: 10767344), and has been identified in >2% of European (Finnish) chromosomes and 9 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Arg245Gln variant may not impact protein function (PMID: 10767344). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as benign for autosomal recessive Refsum disease.

Comment:

South Asian population allele frequency is 1.166% (rs62619919, 389/30616 alleles, 6 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.2.1, this variant is classified as BENIGN. Following criteria are met: BA1

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Using Whole Exome Sequencing to Identify Candidate Genes With Rare Variants In Nonsyndromic Cleft Lip and Palate.	Aylward A	Genetic epidemiology	2016	PMID: 27229527
Structure of human phytanoyl-CoA 2-hydroxylase identifies molecular mechanisms of Refsum disease.	McDonough MA	The Journal of biological chemistry	2005	PMID: 16186124
Molecular basis of Refsum disease: sequence variations in phytanoyl-CoA hydroxylase (PHYH) and the PTS2 receptor (PEX7).	Jansen GA	Human mutation	2004	PMID: 14974078
Human phytanoyl-CoA hydroxylase: resolution of the gene structure and the molecular basis of Refsum's disease.	Jansen GA	Human molecular genetics	2000	PMID: 10767344
http://exac.broadinstitute.org/variant/10-13325784-C-T	-	-	-	-
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PHYH	-	-	-	-

Text-mined citations for rs62619919 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_006214.4(PHYH):c.734G>A (p.Arg245Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs62619919 ...