NM_000277.3:c.293T>C

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP4_ModeratePM2PP3PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.293T>C (p.Leu98Ser) variant in PAH has been reported as homozygous in a Pakistani patient with mild PKU (BH4 deficiency excluded) (PMID:8364546, 9634518, 26542770) This variant has an extremely low frequency in gnomAD v2.1.1 (MAF=0.0001307). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.846. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA114368/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:6U:3O:1

Conservation

PhyloP100: 8.30

Variant links:

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 links:

LOC124902999 (HGNC:):

LOC124902999 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 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 rank	MANE	Protein	UniProt
PAH	NM_000277.3 link	c.293T>C	p.Leu98Ser	missense_variant	Exon 3 of 13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.293T>C	p.Leu98Ser	missense_variant	Exon 4 of 14		NP_001341233.1
PAH	XM_017019370.2 link	c.293T>C	p.Leu98Ser	missense_variant	Exon 3 of 7		XP_016874859.1
LOC124902999	XR_007063428.1 link	n.863-9904A>G		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 link	c.293T>C	p.Leu98Ser	missense_variant	Exon 3 of 13	1	NM_000277.3	ENSP00000448059.1		P00439

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251448

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727216

show subpopulations

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:

0.000162

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6Uncertain:3Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:4Uncertain:1

Nov 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 98 of the PAH protein (p.Leu98Ser). This variant is present in population databases (rs62517167, gnomAD 0.02%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 26542770, 32668217). ClinVar contains an entry for this variant (Variation ID: 627). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PAH protein function with a negative predictive value of 80%. This variant disrupts the p.Leu98 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26322415). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Jan 14, 2022

ClinGen PAH Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.293T>C (p.Leu98Ser) variant in PAH has been reported as homozygous in a Pakistani patient with mild PKU (BH4 deficiency excluded) (PMID: 8364546, 9634518, 26542770) This variant has an extremely low frequency in gnomAD v2.1.1 (MAF=0.0001307). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.846. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_supporting, PP3. -

Jul 27, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 06, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Leu98Ser variant in PAH has been reported in at least 4 individuals with phenylalanine hydroxylase deficiency (mild non-PKU hyperphenylalaninemia, mild PKU) who were either homozygous or compound heterozygous with another pathogenic variant (Guldberg 1993 PMID: 8364546, Bayat 2016 PMID: 26542770, Hillert 2020 PMID: 32668217). It has also been identified in 0.02% (1/4822) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported as likely pathogenic by the ClinGen PAH Variant Curation Expert Panel using the ACMG-AMP criteria specific for phenylalanine hydroxylase variants (Zastrow 2018 PMID: 30311390) and is curated in the FDA-recognized human genetic variant ClinVar database (Variation ID 627). Computational prediction tools and conservation analyses suggest the variant may impact the protein this codon (p.Leu98Val) have been identified in individuals with phenylalanine hydroxylase deficiency and is classified as pathogenic by the ClinGen PAH Variant Curation Expert Panel. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic autosomal recessive phenylalanine hydroxylase deficiency. ACMG/AMP Criteria applied: PM3, PM2_Supporting, PP3, PP4_Moderate, PM5. -

Mar 11, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1Other:1

Sep 10, 2020

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26542770, 8364546, 9634518, 10527663) -

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mild non-PKU hyperphenylalanemia

Pathogenic:1

Jul 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified

Uncertain:1

Jul 18, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PAH c.293T>C (p.Leu98Ser) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251448 control chromosomes (gnomAD). c.293T>C has been reported in the literature in the homozygous state in an individual affected with Hyperphenylalaninemia who has subsequently been cited by others (Guldberg_1993, Bayat_2016, Hillert_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, another variant affecting the same amino acid (L98V) has been observed in at least one affected individual and has been classified as likely pathogenic, suggesting Leu98 may be important for protein function. The following publications have been ascertained in the context of this evaluation (PMID: 26542770, 8364546, 32668217). Four submitters, including the ClinGen PAH Variant Curation Expert Panel, have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1)/likely pathogenic (n=2) and VUS (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic until further clinical and/or functional information becomes available. -

PAH-related disorder

Uncertain:1

Feb 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PAH c.293T>C variant is predicted to result in the amino acid substitution p.Leu98Ser. This variant has been reported in the homozygous state in at least one patient with hyperphenylalaninemia (Guldberg et al. 1993. PubMed ID: 8364546; Bayat et al. 2016. PubMed ID: 26542770; Table S3, Hillert et al. 2020. PubMed ID: 32668217). It has also been listed in an unclassified variant in a large study of patients with hyperphenylalaninemia, although no additional evidence that could help determine the pathogenicity of this variant was provided (Guldberg et al. 1998. PubMed ID: 9634518). A different substitution of the same amino acid (p.Leu98Val) has been reported, in the compound heterozygous state with the common p.Arg408Trp pathogenic variant, in a patient with mild phenylketonuria (Tao et al. 2015. PubMed ID: 26322415). Although we suspect that the c.293T>C (p.Leu98Ser) variant could possibly be pathogenic, at this time its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;T;T;T

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.86

D;D;D;D

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

H;.;.;.

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.6

N;N;N;N

REVEL

Pathogenic

0.85

Sift

Benign

0.047

D;D;D;D

Sift4G

Uncertain

0.032

D;D;T;.

Polyphen

1.0

D;.;.;.

Vest4

0.94

MutPred

0.89

Loss of stability (P = 0.0088);.;Loss of stability (P = 0.0088);Loss of stability (P = 0.0088);

MVP

0.99

MPC

0.25

ClinPred

0.90

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.86

gMVP

0.94

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over