chr12-102852833-G-C

Variant names:

• chr12-102852833-G-C
• rs62508715
• NM_000277.3:c.824C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP4_Moderate PM2 PP3 PM5 PM3

This summary comes from the ClinGen Evidence Repository: The c.824C>G (p.Pro275Arg) variant in PAH is absent from population databases and predicted deleterious by multiple in silico algorithms. It is in the same codon as two previously reported likely pathogenic variants (p.Pro275Ser and p.Pro275Leu). It has been identified in trans with a pathogenic variant (PMID:23514811), and a defect in BH4 metabolism was excluded as a cause of elevated phenylalanine in that patient. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PM5, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229791/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5 O:1
• Conservation: PhyloP100: 10.0

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.824C>G	p.Pro275Arg	missense_variant	Exon 7 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.824C>G	p.Pro275Arg	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.824C>G	p.Pro275Arg	missense_variant	Exon 7 of 13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000307000.7	c.809C>G	p.Pro270Arg	missense_variant	Exon 8 of 14	5		ENSP00000303500.2
PAH	ENST00000549247.6	n.583C>G		non_coding_transcript_exon_variant	Exon 1 of 6	2
PAH	ENST00000635477.1	c.-17C>G		upstream_gene_variant		5		ENSP00000489230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:5

Jul 26, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PAH c.824C>G (p.Pro275Arg) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251346 control chromosomes (gnomAD). c.824C>G has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (examples: Aldamiz-Echevarria_2016). These data indicate that the variant is likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 27121329). Other variants affecting the same codon have been classified pathogenic in ClinVar (CV IDs: 102855, 102853). Three submitters (including ClinGen PAH Variant Curation Expert Panel) have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 30, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 275 of the PAH protein (p.Pro275Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria (PMID: 15464430, 25882749, 27121329). ClinVar contains an entry for this variant (Variation ID: 102854). 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. For these reasons, this variant has been classified as Pathogenic. -

Jan 26, 2018

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 09, 2018

ClinGen PAH Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.824C>G (p.Pro275Arg) variant in PAH is absent from population databases and predicted deleterious by multiple in silico algorithms. It is in the same codon as two previously reported likely pathogenic variants (p.Pro275Ser and p.Pro275Leu). It has been identified in trans with a pathogenic variant (PMID: 23514811), and a defect in BH4 metabolism was excluded as a cause of elevated phenylalanine in that patient. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PM5, PP3. -

not provided Other:1

-

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.5	H;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-8.6	D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.94
MutPred		0.92		Gain of catalytic residue at P275 (P = 0.0194);.;
MVP		1.0
MPC		0.25
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs62508715; hg19: chr12-103246611;