rs62642936

Positions:

chr12-102846932-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3PM3_StrongPS3_SupportingPP4_ModeratePM2

This summary comes from the ClinGen Evidence Repository: The c.932T>C (p.Leu311Pro) variant in PAH has been reported in multiple individuals with PAH deficiency BH4 defect excluded). (PMID:9634518). This variant has an extremely low allele frequency in gnomAD. This variant has enzyme activity <1% in both standard cDNA and intinic systems. This variant was detected with pathogenic variants I65T (PMID:23842451) p.Y386C (PMID:22841515) p.R261Q (PMID:21871829) c.842+5G>A (PMID:19609714) p.Gly257Asp (PMID:26666653) (parental analysis not reported) and in trans with pathogenic variant c.842+1G>A (PMID:27121329) >2 points. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PP4_Moderate, PS3_supporting, PM2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA251524/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:8O:1

Conservation

PhyloP100: 8.94

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PS3

PM2

PM3

PP3

PP4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3 linkuse as main transcript	c.932T>C	p.Leu311Pro	missense_variant	9/13	ENST00000553106.6
PAH	NM_001354304.2 linkuse as main transcript	c.932T>C	p.Leu311Pro	missense_variant	10/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.932T>C	p.Leu311Pro	missense_variant	9/13	1	NM_000277.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152186

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251288

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135802

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461478

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727072

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000900

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:8

Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Dec 02, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 09, 2023	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects PAH function (PMID: 12655546, 17935162, 30037505). 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: 578). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 2615649, 2840952, 9359039, 9634518, 10394930, 21871829). This variant is present in population databases (rs62642936, gnomAD 0.005%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 311 of the PAH protein (p.Leu311Pro). -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 20, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 19, 1988	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 13, 2020	Variant summary: PAH c.932T>C (p.Leu311Pro) 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 2e-05 in 251288 control chromosomes (gnomAD). c.932T>C has been reported in the literature in multiple individuals in affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Rivera_2000, Jeannesson-Thivisol_2015, Aldamiz-Echevarria_2016). These data indicate that the variant is very likely to be associated with disease. At least two in vitro studies report this variant has an impact on protein function and results in <10% of normal PAH activity. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 11, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 17, 2020	- -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Feb 22, 2020	The c.932T>C (p.Leu311Pro) variant in PAH has been reported in multiple individuals with PAH deficiency BH4 defect excluded). (PMID: 9634518). This variant has an extremely low allele frequency in gnomAD. This variant has enzyme activity <1% in both standard cDNA and intinic systems. This variant was detected with pathogenic variants I65T (PMID: 23842451) p.Y386C (PMID: 22841515) p.R261Q (PMID: 21871829) c.842+5G>A (PMID: 19609714) p.Gly257Asp (PMID: 26666653) (parental analysis not reported) and in trans with pathogenic variant c.842+1G>A (PMID: 27121329) >2 points. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PP4_Moderate, PS3_supporting, PM2, PP3. -

not provided

Other:1

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

1.0

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

4.0

H;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-6.8

D;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.99

MVP

1.0

MPC

0.28

ClinPred

1.0

GERP RS

5.4

Varity_R

0.99

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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