12-102844368-C-T

Variant names:

• chr12-102844368-C-T
• rs62516062
• NM_000277.3:c.1033G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP3 PM3 PM5 PM2 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PM2: Absent from controls in ExaC, 100 Genomes, ESP, and gnomAD; PP3: Deleterious effected predicted by SIFT, Polyphen2, and MutationTaster; PM5: A345S (Variant ID 102484) predicted pathogenic in ClinVar; PP4_Moderate: Found in two individuals with Classic PKU on exon 10.Urinary pterin analysis and dihydropteridine reductase (DHPR) assay were performed t (PMID:15503242); PM3: Found in trans with R243Q (pathogenic in ClinVar). (PMID:15503242). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PM5, PP4_Moderate, PM3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA229291/MONDO:0009861/006

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 U:1 O:1
• Conservation: PhyloP100: 7.91
• Publications: 14 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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 rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.1033G>A	p.Ala345Thr	missense_variant	Exon 10 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.1033G>A	p.Ala345Thr	missense_variant	Exon 11 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.1033G>A	p.Ala345Thr	missense_variant	Exon 10 of 13	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461418 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727038

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111636

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:4 Uncertain:1

Aug 30, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: reference population

Jan 24, 2025

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000277.1(PAH):c.1033G>A(A345T) is a missense variant classified as pathogenic in the context of phenylalanine hydroxylase deficiency. A345T has been observed in cases with relevant disease (PMID: 26600521, 32668217, 32893076, 30050108, 30459323, 26322415, 23932990, 36849017, 38105685, 29499199, 33564846, 15503242). Relevant functional assessments of this variant are not available in the literature. A345T has not been observed in referenced population frequency databases. In summary, NM_000277.1(PAH):c.1033G>A(A345T) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Aug 10, 2018

ClinGen PAH Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

PAH-specific ACMG/AMP criteria applied: PM2: Absent from controls in ExaC, 100 Genomes, ESP, and gnomAD; PP3: Deleterious effected predicted by SIFT, Polyphen2, and MutationTaster; PM5: A345S (Variant ID 102484) predicted pathogenic in ClinVar; PP4_Moderate: Found in two individuals with Classic PKU on exon 10.Urinary pterin analysis and dihydropteridine reductase (DHPR) assay were performed t (PMID:15503242); PM3: Found in trans with R243Q (pathogenic in ClinVar). (PMID:15503242). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PM5, PP4_Moderate, PM3).

Jun 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala345 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17502162, 23430918, 24368688). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAH protein function. ClinVar contains an entry for this variant (Variation ID: 102483). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 15503242, 29499199, 32668217). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 345 of the PAH protein (p.Ala345Thr).

not provided Other:1

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	1.0	D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.7	H;.
PhyloP100		7.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.8	D;D
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Vest4		0.98
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs62516062; hg19: chr12-103238146;