rs1334974448

Positions:

• chr12-102840395-CTTACTG-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_Strong PM3 PP4_Moderate PM2

This summary comes from the ClinGen Evidence Repository: The c.1314_1315+4del6 (p.N438fs) variant is a frameshift variant in exon 12 of 13 of a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1_Strong). Exon 13 encodes 15 amino acids + stop codon = 3.3% of PAH protein length. Along with Exon 12, Exon 13 forms the oligomerization domain (residues 411–452), which is responsible for the dimerization and tetramerization of the enzyme, important for regulation of PAH activity (e.g., positive cooperativity by the substrate, L-Phe, and decreasing PAH activity at low L-Phe concentration) (see PMID:23457044; PMID:22005392). Exon 13 contains the non-truncating Likely Pathogenic p.A447P (Likely Pathogenic by ClinGen PAH VCEP) and Pathogenic p.A447D variants (Likely Pathogenic by ClinGen PAH VCEP; Pathogenic in Clinvar (ID 102595; 4 submitters, 2 stars). Thus PVS1_Strong will be applied for variants resulting in deletion of this exon. The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2).It is listed in ClinVar (variant ID 555797) as Likely Pathogenic by one lab. It has been reported in the published literature in one case (PMID:23514811) with abnormal blood Phe and BH4 deficiency formally excluded (PP4_Moderate); in trans with the p.R138Q variant (Pathogenic per PAH VCEP) (PM3). Classification: PathogenicSupporting Criteria: PVS1_Strong; PM2; PM3; PP4_Moderate LINK:https://erepo.genome.network/evrepo/ui/classification/CA16020994/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH ENST00000553106.6 splice_donor, splice_donor_region, coding_sequence, intron
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 8.81

Genes affected

PAH (HGNC:8582): (phenylalanine hydroxylase) This gene encodes a member of the biopterin-dependent aromatic amino acid hydroxylase protein family. The encoded phenylalanine hydroxylase enzyme hydroxylates phenylalanine to tyrosine and is the rate-limiting step in phenylalanine catabolism. Deficiency of this enzyme activity results in the autosomal recessive disorder phenylketonuria. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3	c.1314_1315+4del		splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, intron_variant	12/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.1314_1315+4del		splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, intron_variant	13/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.1314_1315+4del		splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, intron_variant	12/13	1	NM_000277.3	ENSP00000448059	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	May 21, 2020	The c.1314_1315+4del6 (p.N438fs) variant is a frameshift variant in exon 12 of 13 of a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1_Strong). Exon 13 encodes 15 amino acids + stop codon = 3.3% of PAH protein length. Along with Exon 12, Exon 13 forms the oligomerization domain (residues 411-452), which is responsible for the dimerization and tetramerization of the enzyme, important for regulation of PAH activity (e.g., positive cooperativity by the substrate, L-Phe, and decreasing PAH activity at low L-Phe concentration) (see PMID: 23457044; PMID: 22005392). Exon 13 contains the non-truncating Likely Pathogenic p.A447P (Likely Pathogenic by ClinGen PAH VCEP) and Pathogenic p.A447D variants (Likely Pathogenic by ClinGen PAH VCEP; Pathogenic in Clinvar (ID 102595; 4 submitters, 2 stars). Thus PVS1_Strong will be applied for variants resulting in deletion of this exon. The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It is listed in ClinVar (variant ID 555797) as Likely Pathogenic by one lab. It has been reported in the published literature in one case (PMID: 23514811) with abnormal blood Phe and BH4 deficiency formally excluded (PP4_Moderate); in trans with the p.R138Q variant (Pathogenic per PAH VCEP) (PM3). Classification: Pathogenic Supporting Criteria: PVS1_Strong; PM2; PM3; PP4_Moderate -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 21, 2017	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1334974448; hg19: chr12-103234173;