rs539743701

Positions:

• chr12-102866642-G-A

Variant summary

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

This summary comes from the ClinGen Evidence Repository: This c.463C>T (p.Arg155Cys) variant in PAH was reported in at least one patient with mild HPA detected in trans with pathogenic variant p.Gly289Arg (PMID:27121329). A defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels as well as by measuring the dihydropteridine reductase activity. Computational evidence supports a deleterious effect. This variant is observed at an amino acid residue where two other pathogenic missense variants have also been observed. This variant is seen at an extremely low frequency in population databases. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM5, PM3, PM2, PP4_moderate, and PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6748917/MONDO:0009861/006

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6 U:1
• Conservation: PhyloP100: 2.87

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 (HGNC:):

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/exons	MANE	Protein	UniProt
PAH	NM_000277.3	c.463C>T	p.Arg155Cys	missense_variant	5/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.463C>T	p.Arg155Cys	missense_variant	6/14		NP_001341233.1
PAH	XM_017019370.2	c.463C>T	p.Arg155Cys	missense_variant	5/7		XP_016874859.1
LOC124902999	XR_007063428.1	n.807+1415G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.463C>T	p.Arg155Cys	missense_variant	5/13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000549111.5	n.559C>T		non_coding_transcript_exon_variant	5/6	1
PAH	ENST00000307000.7	c.448C>T	p.Arg150Cys	missense_variant	6/14	5		ENSP00000303500.2
PAH	ENST00000551988.5	n.530+10820C>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251344 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135834

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461364 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727010

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74410

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:6 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 06, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 26, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 15, 2022	Variant summary: PAH c.463C>T (p.Arg155Cys) 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 allele was found at a frequency of 2e-05 in 251344 control chromosomes. c.463C>T has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria; Bueno_2013, Aldamiz-Echevarria_2016, Hillert_2020). Two other variants affecting the same amino acid have been reported in association with Phenylketonuria in HGMD (R155H, R155P). Two clinical diagnostic laboratories and one expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation: two submitters classified the variant as VUS and pathogenic, respectively while the ClinGen PAH Variant Curation Expert Panel classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 14, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 08, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 10, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg155 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18937047, 23932990, 24401910, 26210745, 28754886). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 554011). This missense change has been observed in individual(s) with phenylketonuria (PMID: 23514811). This variant is present in population databases (rs539743701, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 155 of the PAH protein (p.Arg155Cys). -
Likely pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Oct 15, 2020	This c.463C>T (p.Arg155Cys) variant in PAH was reported in at least one patient with mild HPA detected in trans with pathogenic variant p.Gly289Arg (PMID: 27121329). A defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels as well as by measuring the dihydropteridine reductase activity. Computational evidence supports a deleterious effect. This variant is observed at an amino acid residue where two other pathogenic missense variants have also been observed. This variant is seen at an extremely low frequency in population databases. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM5, PM3, PM2, PP4_moderate, and PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	1.0	D;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.0	H;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-7.4	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.89		Loss of MoRF binding (P = 0.0021);.;
MVP		0.99
MPC		0.27
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.93

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: rs539743701; hg19: chr12-103260420;