12-102852831-T-C

Position:

• chr12-102852831-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM3_Strong PM2 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.826A>G (p.Met276Val) variant in PAH is absent from population databases. It has been identified in trans with pathogenic variants in two patients (A300S and R261Q; PMID:16198137), and identified in an additional patient in which a defect in BH4 metabolism was excluded as a cause of elevated phenylalanine (PMID:9634518). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229794/MONDO:0009861/006

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 O:1
• Conservation: PhyloP100: 4.98

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 Likely_pathogenic. Variant got 8 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.
• 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.826A>G	p.Met276Val	missense_variant	7/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.826A>G	p.Met276Val	missense_variant	8/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.826A>G	p.Met276Val	missense_variant	7/13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000307000.7	c.811A>G	p.Met271Val	missense_variant	8/14	5		ENSP00000303500.2
PAH	ENST00000549247.6	n.585A>G		non_coding_transcript_exon_variant	1/6	2
PAH	ENST00000635477.1	c.-15A>G		upstream_gene_variant		5		ENSP00000489230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461796 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727200

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: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:4

Likely pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Dec 09, 2018	The c.826A>G (p.Met276Val) variant in PAH is absent from population databases. It has been identified in trans with pathogenic variants in two patients (A300S and R261Q; PMID: 16198137), and identified in an additional patient in which a defect in BH4 metabolism was excluded as a cause of elevated phenylalanine (PMID: 9634518). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 08, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 04, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 30, 2023	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 276 of the PAH protein (p.Met276Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 8068076, 16290003; Invitae). ClinVar contains an entry for this variant (Variation ID: 102856). 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. For these reasons, this variant has been classified as Pathogenic. -

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	Benign	0.18
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.90	D;D
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T;T
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.8	N;N
REVEL	Pathogenic	0.79
Sift	Uncertain	0.015	D;D
Sift4G	Uncertain	0.042	D;T
Polyphen		0.27	B;.
Vest4		0.86
MutPred		0.88		Loss of solvent accessibility (P = 0.0217);.;
MVP		0.95
MPC		0.040
ClinPred		0.94	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.92

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: rs62516149; hg19: chr12-103246609;