rs62514929

Positions:

• chr12-102855209-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM3 PVS1 PM2 PP4

This summary comes from the ClinGen Evidence Repository: The c.632delC (p.Pro211Hisfs) variant in PAH leads to a frameshift at amino acid 211/432. It is identified with low frequency in population databases (1.648e-5). It has been identified in two individuals with Phenylketonuria as a homozygous variant and in trans with c.1066-11G>A (PMID:26413448; 26666653). It has been described in multiple patients with PKU, although a defect in BH4 metabolism has not been excluded as a cause of elevated phenylalanine in any case. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229667/MONDO:0009861/006

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PAH ENST00000553106.6 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:6 O:1
• Conservation: PhyloP100: 8.15

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 13 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.632del	p.Pro211HisfsTer130	frameshift_variant	6/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.632del	p.Pro211HisfsTer130	frameshift_variant	7/14		NP_001341233.1
PAH	XM_017019370.2	c.632del	p.Pro211HisfsTer60	frameshift_variant	6/7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.632del	p.Pro211HisfsTer130	frameshift_variant	6/13	1	NM_000277.3	ENSP00000448059	P1
PAH	ENST00000549111.5	n.728del		non_coding_transcript_exon_variant	6/6	1
PAH	ENST00000307000.7	c.617del	p.Pro206HisfsTer130	frameshift_variant	7/14	5		ENSP00000303500

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251336 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135830

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461846 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	This sequence change creates a premature translational stop signal (p.Pro211Hisfs*130) in the PAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is present in population databases (rs62514929, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with clinical features of hyperphenylalaninemia (PMID: 8659548, 26413448). ClinVar contains an entry for this variant (Variation ID: 102767). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Dec 09, 2018	The c.632delC (p.Pro211Hisfs) variant in PAH leads to a frameshift at amino acid 211/432. It is identified with low frequency in population databases (1.648e-5). It has been identified in two individuals with Phenylketonuria as a homozygous variant and in trans with c.1066-11G>A (PMID: 26413448; 26666653). It has been described in multiple patients with PKU, although a defect in BH4 metabolism has not been excluded as a cause of elevated phenylalanine in any case. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 30, 2020	Variant summary: PAH c.632delC (p.Pro211HisfsX130) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251336 control chromosomes. c.632delC has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Jeannesson-Thivisol_2015, Biglari_2015, Guldberg_1996). These data indicate that the variant is likely to be associated with disease. At least one publication reports indirect experimental evidence as having been identified in homozygosity in a patient with a confirmed biochemical, enzymatic and clinical diagnosis of classic PAH (example, Biglari_2015). One clinical diagnostic laboratory and one expert panel (ClinGen PAH Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 05, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 17, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 14, 2019	- -

not provided Other:1

not provided, no classification provided

literature only

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

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Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs62514929; hg19: chr12-103248987;