rs62516109

Positions:

• chr12-102855204-A-G

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The c.638T>C (p.Leu213Pro) variant in PAH has been reported in in 4 patients with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID:8659548; PMID:19292873; PMID:21147011). This variant is absent from large population studies (PM2; http://exac.broadinstitute.org). This variant was detected in trans with c.1066-11G>A, E390G, D415N, R261X.(Pathogenic in ClinVar) (PM3_Very-strong; PMID:19292873; PMID:21147011; PMID:8632937). Computational prediction tools and conservation analysis suggest that the c.638T>C variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_Very-strong LINK:https://erepo.genome.network/evrepo/ui/classification/CA273109/MONDO:0009861/006

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:10 O:1
• Conservation: PhyloP100: 9.32

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 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/exons	MANE	Protein	UniProt
PAH	NM_000277.3	c.638T>C	p.Leu213Pro	missense_variant	6/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.638T>C	p.Leu213Pro	missense_variant	7/14		NP_001341233.1
PAH	XM_017019370.2	c.638T>C	p.Leu213Pro	missense_variant	6/7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.638T>C	p.Leu213Pro	missense_variant	6/13	1	NM_000277.3	ENSP00000448059	P1
PAH	ENST00000549111.5	n.734T>C		non_coding_transcript_exon_variant	6/6	1
PAH	ENST00000307000.7	c.623T>C	p.Leu208Pro	missense_variant	7/14	5		ENSP00000303500

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000150 AC: 22 AN: 1461858 Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 10 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:7

Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Oct 01, 2018	The c.638T>C (p.Leu213Pro) variant in PAH has been reported in in 4 patients with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID: 8659548; PMID: 19292873; PMID: 21147011). This variant is absent from large population studies (PM2; http://exac.broadinstitute.org). This variant was detected in trans with c.1066-11G>A, E390G, D415N, R261X.(Pathogenic in ClinVar) (PM3_Very-strong; PMID: 19292873; PMID: 21147011; PMID: 8632937). Computational prediction tools and conservation analysis suggest that the c.638T>C variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_Very-strong -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 27, 2024	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jul 18, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 14, 2018	Across a selection of the available literature, the PAH c.638T>C (p.Leu213Pro) missense variant has been reported in seven individuals with phenylalanine hydroxylase (PAH) deficiency, including in six who carried the variant in a compound heterozygous state with a second variant and in one who was heterozygous for the variant with no second identified variant (Guldberg et al. 1996; Tyfield et al. 1997; Bosco et al. 1998; Daniele et al. 2009; Utz et al. 2012; Djordjevic et al. 2012; Polak et al. 2013). Of the compound heterozygotes, five presented with a classic phenylketonuria (PKU) phenotype, while the remaining compound heterozygote and the heterozygote both presented a mild hyperphenylalaninemia phenotype. Control data are unavailable for this variant which is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium, or the Genome Aggregation Database in a region of good sequence coverage so the variant is presumed to be rare. Based on the collective evidence, the p.Leu213Pro variant is classified as pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 23, 2021	Variant summary: PAH c.638T>C (p.Leu213Pro) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain 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 251336 control chromosomes. c.638T>C has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) in the homozygous and compound heterozygous state (Koch_1997, Sarkissian_2011, Jeannesson-Thivisol_2015, Shirzadeh_2018, etc). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 14, 2024	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 213 of the PAH protein (p.Leu213Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria (PMID: 8632937, 9521426, 19292873, 22112818, 23430547). ClinVar contains an entry for this variant (Variation ID: 92747). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2019	- -
not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 14, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Tetrahydrobiopterin (BH4) responsiveness is inconsistent (Sarkissian et al., 2012; Djordjevic et al., 2013); This variant is associated with the following publications: (PMID: 9521426, 22112818, 23764561, 25750018, 23430918, 8659548, 23430547, 26666653, 19292873, 32668217, 35405047) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	1.0	D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.7	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.7	D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.93		Loss of stability (P = 0.0406);.;
MVP		1.0
MPC		0.28
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.99
gMVP		1.0

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: rs62516109; hg19: chr12-103248982;