rs62642939

Variant names:

• chr12-102851709-C-A
• rs62642939
• NM_000277.3:c.890G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-102851709-C-A
• chr12-102851709-C-G
• chr12-102851709-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000277.3(PAH):​c.890G>T​(p.Arg297Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R297C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 3.05

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 18 ACMG points.

• PM1: In a helix (size 13) in uniprot entity PH4H_HUMAN there are 29 pathogenic changes around while only 0 benign (100%) in NM_000277.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-102851710-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 12-102851709-C-A is Pathogenic according to our data. Variant chr12-102851709-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 805823.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.890G>T	p.Arg297Leu	missense_variant	Exon 8 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.890G>T	p.Arg297Leu	missense_variant	Exon 9 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.890G>T	p.Arg297Leu	missense_variant	Exon 8 of 13	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461638 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727122

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:3

Apr 30, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with leucine at codon 297 of the PAH protein (p.Arg297Leu). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with hyperphenylalaninemia (PMID: 17096675). ClinVar contains an entry for this variant (Variation ID: 805823). 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. This variant disrupts the p.Arg297 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8807331, 27121329, 23357515, 10234516, 21307867, 9298832, 25596310). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Jul 07, 2019

ClinGen PAH Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.890G>T (p.Arg297Leu) variant in PAH has been reported in at least 1 patient with mild PKU who carried in trans the nonsense variant R243X (BH4 deficiency was not excluded) (PMID: 17096675). This variant is absent from the gnomAD and ESP population databases. Biochemical assays demonstrate a loss of ~50% enzyme activity (PMID: 18346471 & 21820508). Other amino acid changes at this codon have been reported. Overall, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PS3. -

Dec 11, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PAH c.890G>T (p.Arg297Leu) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251036 control chromosomes (gnomAD). c.890G>T has been reported in the literature in at least one individual affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Daniele_2006). In addition, other amino acid changes (R297H, R297C) at this codon have been found in patients with Phenylketonuria (Hillert_2020). These data indicate that the variant is likely to be associated with disease. Functional studies reported experimental evidence evaluating an impact on protein function and this variant effect results in 30%-50% of normal activity (Daniele_2008, Cerreto_2011). The following publications have been ascertained in the context of this evaluation (PMID: 21820508, 17096675, 18346471, 30275481, 32668217). Two submitters, including one expert panel (ClinGen PAH Variant Curation Expert Panel), have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;T
Eigen	Benign	0.073
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	1.6	L;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.58
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.028	D;D
Polyphen		0.063	B;.
Vest4		0.81
MutPred		0.93		Loss of catalytic residue at R297 (P = 0.0517);.;
MVP		0.95
MPC		0.035
ClinPred		0.93	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs62642939; hg19: chr12-103245487;