chr12-102855309-T-C

Variant names:

• chr12-102855309-T-C
• rs77958223
• NM_000277.3:c.533A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2_Supporting PM3_Strong PP3_Moderate PP4_Moderate PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.533A>G variant in PAH is a missense variant predicted to cause substitution of glutamine by glycine at amino acid 178 (p.Glu178Gly). At least 5 patients with this variant displayed serum Phe levels > 6.5–10 mg/dl which is highly specific for PAH deficiency; BH4 deficiency was excluded (PP4_moderate, PMID:18299955, PMID:9634518). Of those individuals, 4 probands were compound heterozygous for the variant and a pathogenic variant and 1 proband was compound heterozygous with a likely pathogenic variant (phase unknown, 2.25 points). The population allele frequency in gnomAD v4.1 is 0.00003965 which is lower than the ClinGen PAH VCEP threshold (<0.0002) for PM2_Supporting, meeting this criterion (PM2_Supporting). The results from in silico predictors [REVEL=0.841], predict a damaging effect on PAH function (PP3_moderate). Enzyme activity assay showed 39% residual phenylalanine hydroxylase activity indicating that this variant impacts protein function (PMID:17935162)(PS3_supporting). In summary, this variant meets criteria to be classified as pathogenic for PAH deficiency in an autosomal recessive manner based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH Expert Panel: PM2_supporting, PP3_moderate, PS3_supporting, PP4_Moderate, PM3_Strong (version 2.0, 11/16/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA273110/MONDO:0009861/006

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:16 O:1
• Conservation: PhyloP100: 5.25
• Publications: 22 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):

• phenylketonuria

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, G2P
• classic phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• maternal phenylketonuria

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

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

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• 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.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	NM_000277.3	MANE Select	c.533A>G	p.Glu178Gly	missense	Exon 6 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.533A>G	p.Glu178Gly	missense	Exon 7 of 14	NP_001341233.1	P00439

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	ENST00000553106.6	TSL:1 MANE Select	c.533A>G	p.Glu178Gly	missense	Exon 6 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000549111.5	TSL:1	n.629A>G		non_coding_transcript_exon	Exon 6 of 6
	PAH	ENST00000906695.1		c.533A>G	p.Glu178Gly	missense	Exon 6 of 14	ENSP00000576754.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000716 AC: 18 AN: 251232 AF XY: 0.0000663

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000342 AC: 50 AN: 1461844 Hom.: 0 Cov.: 34 AF XY: 0.0000316 AC XY: 23 AN XY: 727226

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.0000671 AC: 3 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000387 AC: 43 AN: 1111990

Other (OTH) AF: 0.0000497 AC: 3 AN: 60392

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152148 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74322

African (AFR) AF: 0.0000724 AC: 3 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000566 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
7	-	-	Phenylketonuria (7)
6	-	-	not provided (7)
1	-	-	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	PAH-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		5.3
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.64	P
Vest4		0.58
MutPred		0.88		Loss of catalytic residue at E178 (P = 0.0599)
MVP		0.98
MPC		0.073
ClinPred		0.64	D
GERP RS		5.7
Varity_R		0.68
gMVP		0.86
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs77958223; hg19: chr12-103249087;