12-102852929-C-T

Variant names:

• chr12-102852929-C-T
• rs62508588
• NM_000277.3:c.728G>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000277.3(PAH):​c.728G>A​(p.Arg243Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R243L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20 O:1
• Conservation: PhyloP100: 7.91
• Publications: 152 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 15 ACMG points.

• PM1: In a hotspot region, there are 29 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000277.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-102852929-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 102808.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 440 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: -0.64755 (below the threshold of 3.09). Trascript score misZ: -0.0084567 (below the threshold of 3.09). GenCC associations: The gene is linked to phenylketonuria, tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria, maternal phenylketonuria, classic phenylketonuria, mild phenylketonuria, mild hyperphenylalaninemia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917
• PP5: Variant 12-102852929-C-T is Pathogenic according to our data. Variant chr12-102852929-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.728G>A	p.Arg243Gln	missense_variant	Exon 7 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.728G>A	p.Arg243Gln	missense_variant	Exon 8 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.728G>A	p.Arg243Gln	missense_variant	Exon 7 of 13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000307000.7	c.713G>A	p.Arg238Gln	missense_variant	Exon 8 of 14	5		ENSP00000303500.2
PAH	ENST00000549247.6	n.487G>A		non_coding_transcript_exon_variant	Exon 1 of 6	2
PAH	ENST00000635477.1	c.-113G>A		upstream_gene_variant		5		ENSP00000489230.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152042 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000757 AC: 19 AN: 251112 AF XY: 0.0000516

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000451 AC: 66 AN: 1461840 Hom.: 0 Cov.: 32 AF XY: 0.0000454 AC XY: 33 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.000179 AC: 8 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000360 AC: 40 AN: 1111984

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74378

African (AFR) AF: 0.00 AC: 0 AN: 41526

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5158

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4802

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000560 Hom.: 0

Bravo AF: 0.0000453

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Phenylketonuria Pathogenic:14

Nov 03, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PAH c.728G>A (p.Arg243Gln) variant located in the aromatic amino acid hydroxylase, C-terminal (InterPro) involves the alteration of a conserved nucleotide and 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 19/245876 control chromosomes at a frequency of 0.0000773, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). The variant of interest has been reported in multiple publications in affected compound heterozygote and homozygote individuals presenting with classic PKU, mild PKU, HPA, and mild-HPA. Activity levels for these affected individuals were indicated to have been significantly reduced in comparison to wild type (Aldamiz-Echevarria_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 10, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.728G>A;p.(Arg243Gln) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 591; PMID: 29499199; 28676969; 24401910; 14722928) - PS4. The variant is present at low allele frequencies population databases (rs62508588– gnomAD 0.0002631%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Arg243Gln) was detected in trans with a Pathogenic variant (PMID: 24401910; 14722928) - PM3_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic -

-

Biochemistry Laboratory of CDMU, Chengde Medical University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

- -

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 243 of the PAH protein (p.Arg243Gln). This variant is present in population databases (rs62508588, gnomAD 0.03%). This missense change has been observed in individual(s) with phenylketonuria (PKU) (PMID: 2071149, 23716935, 24401910, 24705691, 27264808). ClinVar contains an entry for this variant (Variation ID: 591). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PAH protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 12655546, 21953985, 23500595). For these reasons, this variant has been classified as Pathogenic. -

Nov 21, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 14, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 19, 2023

Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2016

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3_Supporting+PM3_VeryStrong+PP4_Moderate -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 18, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

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

PS3+PM3_VS+PP1_S+PP3+PP4_M -

not provided Pathogenic:4 Other:1

Apr 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 07, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported to be associated with approximately 10-18% residual phenylalanine hydroxylase activity compared to wild-type (Shi et al., 2012; Couce et al., 2013; Liang et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported to be responsive to tetrahydrobiopterin (BH4) therapy (Zurfluh et al. 2008); This variant is associated with the following publications: (PMID: 28851938, 28676969, 17935162, 24401910, 2071149, 27264808, 25750018, 23500595, 21953985, 12655546, 29317692, 29499199, 11243094, 30037505, 29909188, 30648773, 31178897, 30678510, 31355225, 30747360, 31998365, 30275481, 34426522, 33677757, 31589614, 32778825, 33465300, 29288420, 33375644) -

-

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 07, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in potentially important domain of the protein. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. -

PAH-related disorder Pathogenic:1

Jun 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PAH c.728G>A variant is predicted to result in the amino acid substitution p.Arg243Gln. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with phenylketonuria (Couce et al. 2013. PubMed ID: 23500595; Table 2, Ghanei et al. 2023. PubMed ID: 36646061) and is one of the most common pathogenic PAH variants in the Chinese population (see for example, Lee et al. 2004. PubMed ID: 15503242; Song et al. 2005. PubMed ID: 16256386; Liang et al. 2014. PubMed ID: 24401910). This variant is reported in 0.038% of alleles in individuals of East Asian decent in gnomAD. In vitro experimental studies suggest this variant reduces enzyme activity to ~10-20% of control (Table 1, Shi et al. 2012. PubMed ID: 21953985; Couce et al. 2013. PubMed ID: 23500595; Liang et al. 2014. PubMed ID: 24401910). This variant is classified as pathogenic and likely pathogenic in ClinVar by multiple outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/591/). Taken together, we classify this variant as pathogenic. -

Inborn genetic diseases Pathogenic:1

Jan 27, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M;.
PhyloP100		7.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.015	D;D
Polyphen		1.0	D;.
Vest4		0.95
MVP		0.98
MPC		0.25
ClinPred		0.94	D
GERP RS		5.9
PromoterAI		-0.044	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.95
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs62508588; hg19: chr12-103246707;