rs62642928

Positions:

• chr12-102912838-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS3 PM3 PP4_Moderate PM2

This summary comes from the ClinGen Evidence Repository: The c.121C>T (p.Leu41Phe) variant in PAH has been reported in 2 individuals with mild PKU (BH4 deficiency excluded). (PMID:21147011, 8268925). This variant is absent in population databases. This variant has 10% enzyme activity PMID:21953985. This variant was detected with IVS10-11G>A (PMID:21147011) and R261Q (PMID:8268925)). Computational prediction tools are conflicting. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM2, PM3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229401/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:2 O:1
• Conservation: PhyloP100: 4.58

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 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.
• 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.121C>T	p.Leu41Phe	missense_variant	2/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.121C>T	p.Leu41Phe	missense_variant	3/14		NP_001341233.1
PAH	XM_017019370.2	c.121C>T	p.Leu41Phe	missense_variant	2/7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.121C>T	p.Leu41Phe	missense_variant	2/13	1	NM_000277.3	ENSP00000448059	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 10, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu41 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 8830172, 10679941), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects PAH function (PMID: 11708866). 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. ClinVar contains an entry for this variant (Variation ID: 102569). This missense change has been observed in individual(s) with mild phenylketonuria and PAH-related disease (PMID: 8268925, 8830172, 9399896, 26503515, 32668217; BIOPKU http://www.biopku.org). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 41 of the PAH protein (p.Leu41Phe). -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Jun 01, 2020	The c.121C>T (p.Leu41Phe) variant in PAH has been reported in 2 individuals with mild PKU (BH4 deficiency excluded). (PMID: 21147011, 8268925). This variant is absent in population databases. This variant has 10% enzyme activity PMID: 21953985. This variant was detected with IVS10-11G>A (PMID: 21147011) and R261Q (PMID: 8268925)). Computational prediction tools are conflicting. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM2, PM3. -

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	0.65
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;D;D;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.4	N;N;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0040	D;D;T;D
Sift4G	Uncertain	0.0050	D;D;D;.
Polyphen		0.99	D;.;.;.
Vest4		0.90
MutPred		0.89		Gain of methylation at K42 (P = 0.0383);.;Gain of methylation at K42 (P = 0.0383);Gain of methylation at K42 (P = 0.0383);
MVP		0.99
MPC		0.23
ClinPred		0.98	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.75

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: rs62642928; hg19: chr12-103306616;