VCV001327563.1 - ClinVar

NM_000277.3(PAH):c.914_1199+1del

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Likely pathogenic

for Phenylketonuria

Classification is based on the expert panel submission

Jul 2021 by ClinGen PAH Variant Curation Expert Panel

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

FDA Recognized Database

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000277.3(PAH):c.914_1199+1del

Variation ID: 1327563 Accession: VCV001327563.1

Type and length

Deletion, 3,306 bp

Location

Cytogenetic: 12q23.2 12: 102843645-102846950 (GRCh38) [ NCBI UCSC ] 12: 103237423-103240728 (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	Dec 18, 2021	Dec 18, 2021	Jul 25, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_000277.3:c.914_1199+1del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor splice donor
NM_001354304.2:c.914_1199+1del		splice acceptor splice donor
NC_000012.12:g.102843648_102846953del
NC_000012.11:g.103237426_103240731del
NG_008690.2:g.116461_119766del

... more HGVS ... less HGVS

Protein change

Other names

NM_001354304.2:c.914_1199+1del

Canonical SPDI

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.

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

Links

ClinGen: CA251545 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		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	1570	1700

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.
Phenylketonuria	Likely pathogenic (1)	reviewed by expert panel	Jul 25, 2021	RCV001789825.1

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.
Likely pathogenic (Jul 25, 2021) C Contributing to aggregate classification	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: SCV002032224.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/424fcc27-3ba4-4f62-ac78-76b5991ae696 Comment: The g.~6.7kbdel (p.Ex9_11del; c.914_1199+1del; CA251545) in PAH is a large deletion involving exons 9, 10, and 11. The deletion removed exons 9-11 but spared exon … (more) The g.~6.7kbdel (p.Ex9_11del; c.914_1199+1del; CA251545) in PAH is a large deletion involving exons 9, 10, and 11. The deletion removed exons 9-11 but spared exon 12 in long-range PCR (see PMID: 10472529). This region is critical to protein function, as exons 9 and 10 form part of the PAH catalytic domain, and include key amino acid residues. Therefore, this is a multi-exon deletion that disrupts the reading frame and is NOT predicted to undergo NMD, which truncates/alters a critical region for protein function. Thus, PVS1_Strong is applied. It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It has been previously reported in one case with mild PKU (per abnormal blood Phe levels; BH4 deficiency does not appear to have been formally excluded) (PP4), in confirmed trans with the p.E390G variant (Likely Pathogenic per PAH VCEP) (PMID: 10472529) (PM3). Classification: Likely Pathogenic Supporting Criteria: PVS1_Strong; PM2; PM3; PP4 (less)

Comment:

The g.~6.7kbdel (p.Ex9_11del; c.914_1199+1del; CA251545) in PAH is a large deletion involving exons 9, 10, and 11. The deletion removed exons 9-11 but spared exon 12 in long-range PCR (see PMID: 10472529). This region is critical to protein function, as exons 9 and 10 form part of the PAH catalytic domain, and include key amino acid residues. Therefore, this is a multi-exon deletion that disrupts the reading frame and is NOT predicted to undergo NMD, which truncates/alters a critical region for protein function. Thus, PVS1_Strong is applied. It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It has been previously reported in one case with mild PKU (per abnormal blood Phe levels; BH4 deficiency does not appear to have been formally excluded) (PP4), in confirmed trans with the p.E390G variant (Likely Pathogenic per PAH VCEP) (PMID: 10472529) (PM3). Classification: Likely Pathogenic Supporting Criteria: PVS1_Strong; PM2; PM3; PP4

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
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/424fcc27-3ba4-4f62-ac78-76b5991ae696	-	-	-	-

Text-mined citations for this variant ...

Record last updated Apr 08, 2025

ClinVar Genomic variation as it relates to human health

NM_000277.3(PAH):c.914_1199+1del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...