12-102852903-G-C

Position:

• chr12-102852903-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP3 PM5 PS3 PM2 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.754C>G (p.Arg252Gly) variant in PAH has been reported in multiple individuals with Classic PKU (BH4 deficiency excluded). (PP4_Moderate; PMID:1363786, 9634518). This variant is absent in population databases (PM2). This variant has 3% enzyme activity (PS3; PMID:9799096). Computational prediction tools and conservation analysis suggest this variant may impact the protein (PP3). This missense change is at an amino acid residue where different pathogenic missense changes have been seen before (p.Arg252Gln/Trp). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM2, PM5, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229742/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3 O:1
• Conservation: PhyloP100: 3.29

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 11 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.754C>G	p.Arg252Gly	missense_variant	7/13	ENST00000553106.6
PAH	NM_001354304.2	c.754C>G	p.Arg252Gly	missense_variant	8/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.754C>G	p.Arg252Gly	missense_variant	7/13	1	NM_000277.3	P1
PAH	ENST00000307000.7	c.739C>G	p.Arg247Gly	missense_variant	8/14	5
PAH	ENST00000549247.6	n.513C>G		non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:3

Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Dec 08, 2018	The c.754C>G (p.Arg252Gly) variant in PAH has been reported in multiple individuals with Classic PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 1363786, 9634518). This variant is absent in population databases (PM2). This variant has 3% enzyme activity (PS3; PMID: 9799096). Computational prediction tools and conservation analysis suggest this variant may impact the protein (PP3). This missense change is at an amino acid residue where different pathogenic missense changes have been seen before (p.Arg252Gln/Trp). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM2, PM5, PP3. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 18, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 01, 2018	- -

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	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	1.0	D;D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.2	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.7	D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.96		Loss of stability (P = 0.0062);.;
MVP		0.98
MPC		0.26
ClinPred		1.0	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.97
gMVP		0.96

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: rs5030847; hg19: chr12-103246681;