12-102852929-C-T

Position:

• chr12-102852929-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 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:17 O:1
• Conservation: PhyloP100: 7.91

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 16 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000277.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-102852929-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 102808.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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 [Likely_pathogenic]. Clinvar id is 591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-102852929-C-T is described in Lovd as [Pathogenic]. Variant chr12-102852929-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.728G>A	p.Arg243Gln	missense_variant	7/13	ENST00000553106.6
PAH	NM_001354304.2	c.728G>A	p.Arg243Gln	missense_variant	8/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.728G>A	p.Arg243Gln	missense_variant	7/13	1	NM_000277.3	P1
PAH	ENST00000307000.7	c.713G>A	p.Arg238Gln	missense_variant	8/14	5
PAH	ENST00000549247.6	n.487G>A		non_coding_transcript_exon_variant	1/6	2

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

GnomAD3 exomes AF: 0.0000757 AC: 19 AN: 251112 Hom.: 0 AF XY: 0.0000516 AC XY: 7 AN XY: 135708

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 SAS exome AF: 0.00

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000360

Gnomad4 OTH exome AF: 0.0000166

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000574 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:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Phenylketonuria Pathogenic:12

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	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). 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 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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jun 10, 2022	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 -
Pathogenic, no assertion criteria provided	clinical testing	Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	-	PS3+PM3_VS+PP1_S+PP3+PP4_M -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jan 22, 2016	- -
Pathogenic, no assertion criteria provided	case-control	Biochemistry Laboratory of CDMU, Chengde Medical University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 14, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 03, 2017	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1992	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences	Sep 19, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 21, 2022	- -

not provided Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2021	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 07, 2017	- -
not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 31, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2019	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2016

- -

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;.
MutationTaster	Benign	1.0	D;D
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs62508588; hg19: chr12-103246707;