12-102843777-G-T

Variant names:

• chr12-102843777-G-T
• rs62516095
• NM_000277.3:c.1068C>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM3_Strong PP4_Moderate PM2 PVS1

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PM2: gnomAD MAF 0.00017; PP4_Moderate: Detected in PKU patients (PMID:25894915); PM3_Strong: in trans with p.W326X (Pathogenic), and IVS4-1G>A (Pathogenic). (PMID:25894915). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4_Moderate, PM3_Strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA273107/MONDO:0009861/006

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PAH NM_000277.3 stop_gained, splice_region
• Clinical Significance: Pathogenic reviewed by expert panel P:10 O:1
• Conservation: PhyloP100: 1.31
• Publications: 76 publications found

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]

PAH Gene-Disease associations (from GenCC):

• phenylketonuria

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Myriad Women’s Health
• classic phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• maternal phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild hyperphenylalaninemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000277.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	NM_000277.3	MANE Select	c.1068C>A	p.Tyr356*	stop_gained splice_region	Exon 11 of 13	NP_000268.1
	PAH	NM_001354304.2		c.1068C>A	p.Tyr356*	stop_gained splice_region	Exon 12 of 14	NP_001341233.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	ENST00000553106.6	TSL:1 MANE Select	c.1068C>A	p.Tyr356*	stop_gained splice_region	Exon 11 of 13	ENSP00000448059.1
	PAH	ENST00000307000.7	TSL:5	c.1053C>A	p.Tyr351*	stop_gained splice_region	Exon 12 of 14	ENSP00000303500.2
	PAH	ENST00000635477.1	TSL:5	c.171C>A	p.Tyr57*	stop_gained splice_region	Exon 4 of 6	ENSP00000489230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 251004 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461382 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727022

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111776

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:8

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Null variant in a gene where loss of function (LOF) is a known mechanism of disease.;For recessive disorders, detected in trans with a pathogenic variant.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.

Jan 05, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Tyr356*) in the PAH gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs62516095, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with PAH deficiency-related disease (PMID: 7915167, 27264808). ClinVar contains an entry for this variant (Variation ID: 92729). Studies have shown that this premature translational stop signal results in altered splicing, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 10471838). For these reasons, this variant has been classified as Pathogenic.

Sep 18, 2014

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

PVS1+PM2+PM3_VS+PP4_M

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 04, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PAH c.1068C>A (p.Tyr356X) 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. The variant allele was found at a frequency of 1.2e-05 in 245780 control chromosomes (gnomAD). c.1068C>A has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Tao_2015, Eiken_1996). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submissions from clinical diagnostic laboratories and reputable databases (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Aug 13, 2018

ClinGen PAH Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PM2: gnomAD MAF 0.00017; PP4_Moderate: Detected in PKU patients (PMID:25894915); PM3_Strong: in trans with p.W326X (Pathogenic), and IVS4-1G>A (Pathogenic). (PMID:25894915). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4_Moderate, PM3_Strong).

not provided Pathogenic:2 Other:1

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Nov 11, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 05, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Y356X nonsense variant in the PAH gene has been reported as a pathogenic variant in the PAHConsortium database. The Y356X variant has been previously reported in individuals withphenylketonuria (PKU) (Liang et al., 2014; Liu et al., 2015; Chen et al., 2015; Jeannesson-Thivisol etal., 2015). Functional analysis found that Y356X is associated with significantly reduced enzymeactivity compared to wild type (Zurfluh et al., 2008). It has been reported as non-responsive totetrahydrobiopterin (BH4) therapy (Zurfluh et al., 2008; Jeannesson-Thivisol et al., 2015). TheY356X variant is predicted to cause loss of normal protein function either through protein truncationor nonsense-mediated mRNA decay.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		1.3
Vest4		0.97
GERP RS		2.4
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs62516095; hg19: chr12-103237555;