12-102851743-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000277.3(PAH):c.856G>A(p.Glu286Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. E286E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4 O:1
• Conservation: PhyloP100: 7.57

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, 5 uncertain in NM_000277.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 12-102851743-C-T is Pathogenic according to our data. Variant chr12-102851743-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 102880.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102851743-C-T is described in Lovd as [Pathogenic]. Variant chr12-102851743-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.856G>A	p.Glu286Lys	missense_variant	8/13	ENST00000553106.6
PAH	NM_001354304.2	c.856G>A	p.Glu286Lys	missense_variant	9/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.856G>A	p.Glu286Lys	missense_variant	8/13	1	NM_000277.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250962 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135618

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461750 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 286 of the PAH protein (p.Glu286Lys). This variant is present in population databases (rs62508739, gnomAD 0.01%). This missense change has been observed in individual(s) with phenylketonuria (PMID: 14722928, 29499199). ClinVar contains an entry for this variant (Variation ID: 102880). 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%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 02, 2022	Variant summary: PAH c.856G>A (p.Glu286Lys) results in a conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250962 control chromosomes. c.856G>A has been reported in the literature in multiple individuals affected with classical PKU, mild PKU and MHP (eg. Liang_2014, Wang_2018, etc). These data indicate that the variant is very likely to be associated with disease. PAH activity from COS-1 cells transfected with the showed the variant to have <10% PAH activity compared to wild-type (Liang_2014). One diagnostic clinical lab and one expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Dec 09, 2018	The c.856G>A (p.Glu286Lys) variant in PAH is present with low frequency in population databases (1.2e-4), and is predicted to be deleterious using in silico algorithms. It has been identified in trans with pathogenic variants in two independent patients (R243Q, R241C), and has been identified in a patients with Phenylketonuria in which a defect in BH4 metabolism has been excluded (PMID: 14722928, 24401910). Enzyme activity has been measured as 1% of wild type controls (BioPKU). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4_Moderate, PS3, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 06, 2023	- -

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

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	1.0	D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.7	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.96		Gain of methylation at E286 (P = 0.0059);.;
MVP		1.0
MPC		0.25
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs62508739; hg19: chr12-103245521; COSMIC: COSV61014382; COSMIC: COSV61014382;