VCV000102795.27 - ClinVar

NM_000277.3(PAH):c.707-7A>T

Germline

Top reviewed classifications are shown here.

Submission summary:

12 submissions

12 submitters

3 conditions

Reviewed by expert panel

Benign

Aug 2018 by ClinGen PAH Va… FDA Recognized Database

for Phenylketonuria

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000277.3(PAH):c.707-7A>T

Variation ID: 102795 Accession: VCV000102795.27

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q23.2 12: 102852957 (GRCh38) [ NCBI UCSC ] 12: 103246735 (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	Mar 19, 2014	Sep 29, 2024	Aug 10, 2018

HGVS

Nucleotide	Protein	Molecular consequence
NM_000277.3:c.707-7A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001354304.2:c.707-7A>T		intron variant
NC_000012.12:g.102852957T>A
NC_000012.11:g.103246735T>A
NG_008690.2:g.110454A>T

... more HGVS ... less HGVS

Protein change

Other names

NM_000277.2(PAH):c.707-7A>T

Canonical SPDI

NC_000012.12:102852956:T:A

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.

0.02935 (A)

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

The Genome Aggregation Database (gnomAD), exomes 0.00715

Exome Aggregation Consortium (ExAC) 0.00888

The Genome Aggregation Database (gnomAD) 0.02868

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.02876

1000 Genomes Project 0.02935

Trans-Omics for Precision Medicine (TOPMed) 0.03018

1000 Genomes Project 30x 0.03217

Links

ClinGen: CA180267 dbSNP: rs62508624 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.
PAH		-	-	GRCh38 GRCh37	1506	1629

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 provided	Benign/Likely benign (6)	criteria provided, multiple submitters, no conflicts	Jul 24, 2020	RCV000089046.10
not specified	Benign (1)	criteria provided, single submitter	Feb 25, 2014	RCV000153636.8
Phenylketonuria	Benign (5)	reviewed by expert panel	Aug 10, 2018	RCV000274526.22

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 (Aug 10, 2018)	reviewed by expert panel (ClinGen PAH ACMG Specifications v1) Method: curation	Phenylketonuria (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	ClinGen PAH Variant Curation Expert Panel FDA Recognized Database Accession: SCV000852119.4 First in ClinVar: Dec 26, 2017 Last updated: Dec 11, 2022	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ef426544-d234-401a-81e4-5e2f6a9ded0a Comment: PAH-specific ACMG/AMP criteria applied: BA1: Highest MAF=0.10514 in 1000G. 35 homozygotes in ExAC; BP4: HSF: No significant splicing motif alteration detected. This mutation has probably … (more) PAH-specific ACMG/AMP criteria applied: BA1: Highest MAF=0.10514 in 1000G. 35 homozygotes in ExAC; BP4: HSF: No significant splicing motif alteration detected. This mutation has probably no impact on splicing. CADD=1.163344. In summary this variant meets criteria to be classified as benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BA1, BP4). (less)
Benign (Feb 25, 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: SCV000203185.7 First in ClinVar: Jan 29, 2015 Last updated: Jun 28, 2015	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PAH Number of individuals with the variant: 1 Sex: mixed
Benign (Feb 25, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001881880.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Comment: This variant is associated with the following publications: (PMID: 2666653, 27884173)
Benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000629207.7 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000375568.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Benign (Apr 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002797257.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Benign (Jul 24, 2020)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV001470037.2 First in ClinVar: Jan 26, 2021 Last updated: Jan 06, 2024
Likely Benign (Feb 02, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000281274.1 First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016	Comment: Converted during submission to Likely benign.
Benign (May 14, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000696459.1 First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016	Publications: PubMed (2) PubMed: 12644360‚ 26666653 Comment: Variant summary: c.707-7A>T in PAH gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not … (more) Variant summary: c.707-7A>T in PAH gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect a normal splicing pattern, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.008876 (1049/ 118182 chrs tested), predominantly in individuals of African descent (0.08901; 910/ 10224 chrs tested), including 33 homozygotes. The observed frequencies exceed the maximum expected allele frequency for a pathogenic variant of 0.0079 suggesting that it is a benign polymorphism. The variant of interest has been reported in PKU individuals without strong evidence for causality, but is cited as Benign by a reputable database/clinical laboratory. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. (less)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005235497.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Nov 14, 2019)	no assertion criteria provided Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002088647.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: not provided	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE Accession: SCV000119651.1 First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014
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Comment:

PAH-specific ACMG/AMP criteria applied: BA1: Highest MAF=0.10514 in 1000G. 35 homozygotes in ExAC; BP4: HSF: No significant splicing motif alteration detected. This mutation has probably no impact on splicing. CADD=1.163344. In summary this variant meets criteria to be classified as benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BA1, BP4).

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

Variant summary: c.707-7A>T in PAH gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect a normal splicing pattern, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.008876 (1049/ 118182 chrs tested), predominantly in individuals of African descent (0.08901; 910/ 10224 chrs tested), including 33 homozygotes. The observed frequencies exceed the maximum expected allele frequency for a pathogenic variant of 0.0079 suggesting that it is a benign polymorphism. The variant of interest has been reported in PKU individuals without strong evidence for causality, but is cited as Benign by a reputable database/clinical laboratory. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign.

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
Genotype-phenotype associations in French patients with phenylketonuria and importance of genotype for full assessment of tetrahydrobiopterin responsiveness.	Jeannesson-Thivisol E	Orphanet journal of rare diseases	2015	PMID: 26666653
Phenylalanine hydroxylase gene in psychiatric patients: screening and functional assay of mutations.	Richardson MA	Biological psychiatry	2003	PMID: 12644360
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PAH	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ef426544-d234-401a-81e4-5e2f6a9ded0a	-	-	-	-

Text-mined citations for rs62508624 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000277.3(PAH):c.707-7A>T

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs62508624 ...