12-102852920-G-T

Position:

• chr12-102852920-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3 PP4 PM2 PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.737C>A (p.Ala246Asp) variant in PAH has been reported in 2 patients with PKU (PMID:9012412,12173030), detected with pathogenic variant p.R408W in one patient (PMID:31623983). This variant is absent in population databases. A deleterious effect is predicted by multiple lines of computational evidence. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PP3, PM3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229726/MONDO:0009861/006

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1 O:1
• Conservation: PhyloP100: 10.0

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 Uncertain_significance. Variant got 5 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.737C>A	p.Ala246Asp	missense_variant	7/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.737C>A	p.Ala246Asp	missense_variant	8/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.737C>A	p.Ala246Asp	missense_variant	7/13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000307000.7	c.722C>A	p.Ala241Asp	missense_variant	8/14	5		ENSP00000303500.2
PAH	ENST00000549247.6	n.496C>A		non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461854 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727228

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:1 Uncertain:1

Uncertain significance, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Nov 13, 2020	The c.737C>A (p.Ala246Asp) variant in PAH has been reported in 2 patients with PKU (PMID: 9012412,12173030), detected with pathogenic variant p.R408W in one patient (PMID: 31623983). This variant is absent in population databases. A deleterious effect is predicted by multiple lines of computational evidence. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PP3, PM3_supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 05, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala246 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 32668217), which suggests that this may be a clinically significant amino acid residue. 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: 102812). This missense change has been observed in individual(s) with phenylketonuria (PKU) (PMID: 32668217; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 246 of the PAH protein (p.Ala246Asp). -

not provided Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2015	The A246D missense variants in the PAH gene has been reported as a pathogenicvariant in the PAH Consortium database. The A246D substitution was reported in a patient withphenylketonuria (PKU) from Western Scotland (Tyfield et al., 1997). To our knowledge, information onthe phenotype of patients harboring the A246D variant has not been published. A246D is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residuesdiffer in polarity, charge, size and/or other properties, and a missense variant at the same position(A246V) and in many nearby residues (R243L/Q, P244L, V245L/E/A, G247S/R/V/D, L248R/P,L249F/P/H) have been reported in the Human Gene Mutation Database in association with PKU (Stensonet al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpretA246D to be a pathogenic variant. -
not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.94		Loss of catalytic residue at A246 (P = 0.0266);.;
MVP		0.99
MPC		0.28
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.96

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: rs199475610; hg19: chr12-103246698;