rs62517198

Positions:

• chr12-102855207-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP3 PP4 PM3 PM2 PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.635T>C (p.Leu212Pro) variant in PAH has been reported in multiple individuals with PAH deficiency (PMID:9781015) detected with pathogenic variants: p.R408W (PMID:17502162); p.R158Q (PMID:23430918); c.1066-11G>A (PMID:26666653). This variant is absent in population databases. In vitro residual activity of the p.L212P mutant enzyme is 17% of wild type, and it also showed reduced protein expression. Computational prediction tools and conservation analysis support a deleterious effect on the protein. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3_supporting, PM2, PM3, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229668/MONDO:0009861/006

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5 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]

PAH (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3	c.635T>C	p.Leu212Pro	missense_variant	6/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.635T>C	p.Leu212Pro	missense_variant	7/14		NP_001341233.1
PAH	XM_017019370.2	c.635T>C	p.Leu212Pro	missense_variant	6/7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.635T>C	p.Leu212Pro	missense_variant	6/13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000549111.5	n.731T>C		non_coding_transcript_exon_variant	6/6	1
PAH	ENST00000307000.7	c.620T>C	p.Leu207Pro	missense_variant	7/14	5		ENSP00000303500.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461856 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 21, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 09, 2023	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: 102768). This missense change has been observed in individuals with hyperphenylalaninemia (PMID: 32668217). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 212 of the PAH protein (p.Leu212Pro). Experimental studies have shown that this missense change affects PAH function (PMID: 27620137). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Jul 17, 2021	The c.635T>C (p.Leu212Pro) variant in PAH has been reported in multiple individuals with PAH deficiency (PMID: 9781015) detected with pathogenic variants: p.R408W (PMID: 17502162); p.R158Q (PMID: 23430918); c.1066-11G>A (PMID: 26666653). This variant is absent in population databases. In vitro residual activity of the p.L212P mutant enzyme is 17% of wild type, and it also showed reduced protein expression. Computational prediction tools and conservation analysis support a deleterious effect on the protein. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3_supporting, PM2, PM3, PP3, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 28, 2023	Variant summary: PAH c.635T>C (p.Leu212Pro) 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 251336 control chromosomes. c.635T>C has been reported in the literature as biallelic genotypes in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Fisch_2004, Dobrowolski_2007, Sarkissian_2012, Jeannesson-Thivisol_2015, Hillert_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Trunzo_2016). The most pronounced variant effect results in 17% of normal PAH enzyme activity in vitro. The following publications have been ascertained in the context of this evaluation (PMID: 17502162, 15110327, 32668217, 26666653, 23430918, 27620137). Two clinical diagnostic laboratories and the ClinGen PAH Variant Curation Expert Panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 28, 2017	- -

not provided Other:1

not provided, no classification provided

literature only

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.3	H;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.019	D;D
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.93		Loss of stability (P = 0.0476);.;
MVP		1.0
MPC		0.28
ClinPred		1.0	D
GERP RS		5.6
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: rs62517198; hg19: chr12-103248985;