12-102855279-C-T

Variant names:

• chr12-102855279-C-T
• rs199475689
• NM_000277.3:c.563G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP4_Moderate PP3 PM3

This summary comes from the ClinGen Evidence Repository: The c.563G>A (p.Gly188Asp) variant in PAH has been reported in 3 affected individuals (BH4 deficiency excluded). (PP4_Moderate; PMID:23430918, 26503515, 22526846). This variant is absent in population databases (PM2). This variant was detected with pathogenic variants p.F55fs (parental analysis not reported, PMID:22526846) and p.R243Q (in trans, PMID:26322415; PM3). Computational evidence support a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229628/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5 O:1
• Conservation: PhyloP100: 4.96

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 7 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.
• 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.563G>A	p.Gly188Asp	missense_variant	Exon 6 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.563G>A	p.Gly188Asp	missense_variant	Exon 7 of 14		NP_001341233.1
PAH	XM_017019370.2	c.563G>A	p.Gly188Asp	missense_variant	Exon 6 of 7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.563G>A	p.Gly188Asp	missense_variant	Exon 6 of 13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000549111.5	n.659G>A		non_coding_transcript_exon_variant	Exon 6 of 6	1
PAH	ENST00000307000.7	c.548G>A	p.Gly183Asp	missense_variant	Exon 7 of 14	5		ENSP00000303500.2
PAH	ENST00000551988.5	n.584G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 5	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:5

May 29, 2018

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 188 of the PAH protein (p.Gly188Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyperphenylalaninemia and/or phenylketonuria (PMID: 17557229, 22526846, 29499199, 32668217; Invitae; BIOPKU http://www.biopku.org). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 102738). 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 not expected to disrupt PAH protein function. For these reasons, this variant has been classified as Pathogenic. -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PM3_VeryStrong+PM5_Supporting+PP3_Moderate -

Nov 18, 2019

ClinGen PAH Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.563G>A (p.Gly188Asp) variant in PAH has been reported in 3 affected individuals (BH4 deficiency excluded). (PP4_Moderate; PMID: 23430918, 26503515, 22526846). This variant is absent in population databases (PM2). This variant was detected with pathogenic variants p.F55fs (parental analysis not reported, PMID: 22526846) and p.R243Q (in trans, PMID: 26322415; PM3). Computational evidence support a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. -

Apr 12, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Pathogenic	0.84
Sift	Benign	0.043	D;D
Sift4G	Uncertain	0.058	T;T
Polyphen		0.90	P;.
Vest4		0.89
MutPred		0.87		Loss of MoRF binding (P = 0.0699);.;
MVP		0.99
MPC		0.070
ClinPred		0.97	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.94

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: rs199475689; hg19: chr12-103249057;