12-102843676-T-C

Variant names:

• chr12-102843676-T-C
• rs5030856
• NM_000277.3:c.1169A>G
• PAH p.Glu390Gly

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 20 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PP3_StrongPP5_Very_Strong

The NM_000277.3(PAH):c.1169A>G (p.Glu390Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000985 (AC=159) in the gnomAD database across 1,613,598 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000105. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.02). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000696428: This variant is widely described as one of the frequent pathogenic variants that causes hyperphenylalaninemia with consistent genotype-phenotype data and functional studies. Eight homozygotes with this variant were responsive to BH4 (Dobrowolski_2011) which can be attributed to mild functional effect of this variant." and additional evidence is available in ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.E390= (synonymous): Likely_benign (ClinVar VariationId 1659442, 1 star) This exact variant is curated in the UniProt human variants database as Pathogenic, associated with Phenylketonuria (pku).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:23 O:1
• Conservation: PhyloP100: 8.02
• Publications: 54 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):

• classic phenylketonuria

  Inheritance: AR Classification: DEFINITIVE Submitted by: Natera
• phenylketonuria

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women's Health
• maternal phenylketonuria

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

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Specifications for PAH are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 20 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000696428: This variant is widely described as one of the frequent pathogenic variants that causes hyperphenylalaninemia with consistent genotype-phenotype data and functional studies. Eight homozygotes with this variant were responsive to BH4 (Dobrowolski_2011) which can be attributed to mild functional effect of this variant.; SCV000754075: Experimental studies have shown that this missense change affects PAH function (PMID: 17935162, 22300847, 26803807).; SCV000914554: Averaged across different cell systems, the p.Glu390Gly variant showed 72.7% residual enzyme activity (Zurflüh et al. 2008), while expression in COS-7 cells revealed that the p.\[Glu390Gly\];\[Arg408Trp\] genotype, a recurrent genotype in European and Middle Eastern populations, showed 8.3% residual activity compared to wild type (Danecka et al. 2015).; SCV002047254: Functional studies have shown this variant reduces PAH activity to 42-62% (PMID: 21147011 (2011), 22300847 (2012), 26803807 (2016)).
	PM1Mutational hot spot or critical domain		UniProt domain with ≥4 pathogenic missense and OR ≥ 5 vs. background — hotspot (PM1); In-domain: 10 pathogenic, 0 benign rare missense variants (OR vs. background: 105.0).; ±8 AA neighbourhood: 23 pathogenic, 0 benign (OR vs. background: 235.0).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000105 — very rare for AR gene (base 0.001, raised to 0.00132 by highest known P/LP ClinVar AF 0.00132) — PM2 moderate.
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — strong evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Strong).
	PP5Reputable source reports pathogenic		ClinVar ≥3 stars pathogenic — very strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 3 star(s). ClinVar submissions strongly and reliably favor pathogenicity (23/23 total P/LP).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PAH NM_000277.3	MANE Select	c.1169A>G p.Glu390Gly	missense	Exon 11 of 13	Prot: NP_000268.1 UniProt:
	PAH NM_001354304.2		c.1169A>G p.Glu390Gly	missense	Exon 12 of 14	Prot: NP_001341233.1 UniProt:

PAH NM_000277.3

MANE Select

HGVSc / HGVSpc.1169A>Gp.Glu390Gly

Exon rankExon 11 of 13

missense

Prot: NP_000268.1UniProt: P00439

PAH NM_001354304.2

HGVSc / HGVSpc.1169A>Gp.Glu390Gly

Exon rankExon 12 of 14

missense

Prot: NP_001341233.1UniProt: P00439

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PAH ENST00000553106.6	TSL:1MANE Select	c.1169A>G p.Glu390Gly	missense	Exon 11 of 13	Prot: ENSP00000448059.1 UniProt:
	PAH ENST00000906695.1		c.1268A>G p.Glu423Gly	missense	Exon 12 of 14	Prot: ENSP00000576754.1 UniProt:
	PAH ENST00000906692.1		c.1247A>G p.Glu416Gly	missense	Exon 11 of 13	Prot: ENSP00000576751.1 UniProt:

PAH ENST00000553106.6

TSL:1MANE Select

HGVSc / HGVSpc.1169A>Gp.Glu390Gly

Exon rankExon 11 of 13

missense

Prot: ENSP00000448059.1UniProt: P00439

PAH ENST00000906695.1

HGVSc / HGVSpc.1268A>Gp.Glu423Gly

Exon rankExon 12 of 14

missense

Prot: ENSP00000576754.1UniProt: A0ACI8RXH2

PAH ENST00000906692.1

HGVSc / HGVSpc.1247A>Gp.Glu416Gly

Exon rankExon 11 of 13

missense

Prot: ENSP00000576751.1UniProt: A0ACI8S8A6

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000790	AC:12	Hom:0	AN:151974	Cov:31
GnomAD2 exomes	AF: 0.0000995	AC:25	Hom:	AN:251312	Cov:
GnomAD4 exome	AF: 0.000101	AC:147	Hom:0	AN:1461624	Cov:31
GnomAD4 genome	AF: 0.0000790	AC:12	Hom:0	AN:151974	Cov:31
TOPMed (Bravo)	AF: 0.0000718	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000192	AC:61	Hom:0	AN:317186	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.0000769	AC:1	Hom:	AN:13006	Cov:
Turkish Variome	AF: 0.00142	AC:8	Hom:1	AN:5174	Cov:

Showing 8 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000208 *	2	9622	0.000288 *	3	10428
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28420	0.000139	4	28844
Epi25(Epilepsy)	0.000119	5	41956	0.000120	8	66868
SCHEMA(Schizophrenia)	0.0000660	8	121200	0.0000897	17	189486

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
14	-	-	Phenylketonuria (14)
5	-	-	not provided (6)
2	-	-	Hyperphenylalaninemia (2)
1	-	-	Mild hyperphenylalaninemia (1)
1	-	-	PAH-related disorder (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	22
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Pathogenic	0.81
GPN-Star LLR	N/A	-7.8
GPN-Star score	N/A	7.8
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
Mutation Taster	N/A	4/96	disease causing (ClinVar)
MutationAssessor	Pathogenic	3.1	M
PhyloP100	Pathogenic	8.0
popEVE	Benign	-3.2
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0030	D
Varity_R	N/A	0.77
VESM-3B	Benign	-8.1

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.090
SpliceAI score (max)	Benign	0.15	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs5030856;

hg19: chr12-103237454;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar