rs376480977

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP3PP4PM3PM2

This summary comes from the ClinGen Evidence Repository: The c.1074A>T (p.Leu358Phe) variant in PAH meets criteria to be classified as likely pathogenic. PAH-specific ACMG/AMP criteria applied: PM2: Variant is present at low frequency in gnomAD (0.0000) and ExAC (0.00002). Absent from 1000 Genomes. PM3: Found to co-occur with F331S in one patient with mild HPA, but no additional studies to demonstrate phase of variants (PMID:23764561). Found to co-occur with other non-PKU HPA mutation I306V, phase was not confirmed (PMID:23357515). Found to co-occur in two patients with L348V and R408W with mild and classic PKU, respectively. (PMID:24350308) PP3: Predicted to be damaging (SIFT), probably damaging (PolyPhen2), Disease causing (MutationTaster). PP4: In both studies, patients were recruited for their abnormal Phelevels defined as HPA <600umol or 120-600umol. There was no additional testing done to rule out other similar analyte disorders. PS3_Not Met: Functional studies in E. Coli model used and relative specific activity of L358F is 52+-0.7%, which is above our 50% threshold to apply this line of evidence. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6748747/MONDO:0009861/006

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0780

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

phenylketonuria
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Myriad Women’s Health
classic phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
maternal phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mild hyperphenylalaninemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mild phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PAH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 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.1074A>T	p.Leu358Phe	missense_variant	Exon 11 of 13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.1074A>T	p.Leu358Phe	missense_variant	Exon 12 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 link	c.1074A>T	p.Leu358Phe	missense_variant	Exon 11 of 13	1	NM_000277.3	ENSP00000448059.1		P00439

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251142

AF XY:

0.00000737

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1461536

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727088

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000342

AC:

AN:

1111830

Other (OTH)

AF:

0.0000166

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:5Uncertain:1

Feb 05, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 07, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 22, 2018

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Mar 25, 2024

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.1074A>T (p.Leu358Phe) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) 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 4e-06 in 251142 control chromosomes (gnomAD). c.1074A>T has been reported in the literature in individuals affected with hyperphenylalaninemia (examples: Reblova_2013, Polak_2013, Bik-Multanowski_2022). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 35176108, 28653649, 23764561, 23357515). ClinVar contains an entry for this variant (Variation ID: 556817). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Jul 25, 2021

ClinGen PAH Variant Curation Expert Panel

Significance:Likely pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The c.1074A>T (p.Leu358Phe) variant in PAH meets criteria to be classified as likely pathogenic. PAH-specific ACMG/AMP criteria applied: PM2: Variant is present at low frequency in gnomAD (0.0000) and ExAC (0.00002). Absent from 1000 Genomes. PM3: Found to co-occur with F331S in one patient with mild HPA, but no additional studies to demonstrate phase of variants (PMID: 23764561). Found to co-occur with other non-PKU HPA mutation I306V, phase was not confirmed (PMID: 23357515). Found to co-occur in two patients with L348V and R408W with mild and classic PKU, respectively. (PMID: 24350308) PP3: Predicted to be damaging (SIFT), probably damaging (PolyPhen2), Disease causing (MutationTaster). PP4: In both studies, patients were recruited for their abnormal Phelevels defined as HPA <600umol or 120-600umol. There was no additional testing done to rule out other similar analyte disorders. PS3_Not Met: Functional studies in E. Coli model used and relative specific activity of L358F is 52+-0.7%, which is above our 50% threshold to apply this line of evidence. -

Mar 21, 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 phenylalanine, which is neutral and non-polar, at codon 358 of the PAH protein (p.Leu358Phe). This variant is present in population databases (rs376480977, gnomAD 0.002%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 23357515, 23764561, 24350308; Invitae). ClinVar contains an entry for this variant (Variation ID: 556817). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 28653649). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PAH: PM3:Strong, PM2, PM5, PS3:Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.47

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Benign

0.15

Eigen_PC

Benign

-0.047

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

M;.

PhyloP100

-0.078

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.9

D;D

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.053

T;T

Polyphen

1.0

D;.

Vest4

0.96

MutPred

0.71

Loss of catalytic residue at L358 (P = 0.0296);.;

MVP

0.98

MPC

0.25

ClinPred

0.99

GERP RS

0.33

Varity_R

0.88

gMVP

0.93

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over