rs62514933

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3PP4PP1PM3

This summary comes from the ClinGen Evidence Repository: The c.653G>T (p.Gly218Val) variant in PAH has been reported in multiple individuals with PAH deficiency (PMID:8406445, 9781015, 10479481). This variant has an extremely low allele frequency (MAF=0.00004) in gnomAD. It was detected with multiple pathogenic variants: p.R158Q, p.I65T (PMID:10479481); p.Y414C (PMID:8632937); c.1066-11G>A, p.Arg270Lys, (PMID:26666653); p.P281L (PMID:24368688); p.R408W (PMID:11032331); p.S349P (PMID:22841515); c.1223G > A (p.R408Q) (PMID:29102225). It co-segregated with disease (PKU) in 2 sisters (PMID:8831077). Computational prediction tools and conservation analysis support a deleterious effect on the protein. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP1, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229676/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:9O:1

Conservation

PhyloP100: 7.91

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 7 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.

PP1

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.653G>T	p.Gly218Val	missense_variant	Exon 6 of 13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.653G>T	p.Gly218Val	missense_variant	Exon 7 of 14		NP_001341233.1
PAH	XM_017019370.2 link	c.653G>T	p.Gly218Val	missense_variant	Exon 6 of 7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PAH	ENST00000553106.6 link	c.653G>T	p.Gly218Val	missense_variant	Exon 6 of 13	1	NM_000277.3	ENSP00000448059.1	P00439
PAH	ENST00000549111.5 link	n.749G>T		non_coding_transcript_exon_variant	Exon 6 of 6	1
PAH	ENST00000307000.7 link	c.638G>T	p.Gly213Val	missense_variant	Exon 7 of 14	5		ENSP00000303500.2	J3KND8
PAH	ENST00000551988.5 link	n.*90G>T		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251318

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135814

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000356

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000459

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000496

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:7

Jul 09, 2020

ClinGen PAH Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.653G>T (p.Gly218Val) variant in PAH has been reported in multiple individuals with PAH deficiency (PMID: 8406445, 9781015, 10479481). This variant has an extremely low allele frequency (MAF=0.00004) in gnomAD. It was detected with multiple pathogenic variants: p.R158Q, p.I65T (PMID: 10479481); p.Y414C (PMID: 8632937); c.1066-11G>A, p.Arg270Lys, (PMID: 26666653); p.P281L (PMID: 24368688); p.R408W (PMID: 11032331); p.S349P (PMID: 22841515); c.1223G > A (p.R408Q) (PMID: 29102225). It co-segregated with disease (PKU) in 2 sisters (PMID: 8831077). Computational prediction tools and conservation analysis support a deleterious effect on the protein. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP1, PP3, PP4. -

Dec 04, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 25, 2024

Institute of Immunology and Genetics Kaiserslautern

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG Criteria: PM2, PP3, PS3, PM3, PP5; Variant was found in heterozygous state -

May 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 218 of the PAH protein (p.Gly218Val). This variant is present in population databases (rs62514933, gnomAD 0.004%). This missense change has been observed in individual(s) with phenylketonuria or hyperphenylalaninemia (PMID: 8632937, 10479481, 12655546, 24368688, 26666653). ClinVar contains an entry for this variant (Variation ID: 102773). 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: 12655546). For these reasons, this variant has been classified as Pathogenic. -

Oct 02, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PAH c.653G>T (p.Gly218Val) results in a non-conservative amino acid change located in the catalytic domain (IPR041912) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251318 control chromosomes. c.653G>T has been reported in the literature in multiple compound heterozygous individuals affected with Phenylalanine Hydroxylase Deficiency, including hyperphenylalaninemia and mild-, moderate- and classic forms of phenylketonuria (e.g. Guldberg_1993, Benit_1999, Eisensmith_1996, Pey_2003, Jeannesson-Thivisol_2015). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant causes abnormal oligomerization (Pey_2003) resulting in decreased enzyme function, with about 15-25% residual activity (Benit_1999, Himmelreich_2018). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1Other:1

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PAH p.Gly218Val variant was identified in the compound heterozygous state with another pathogenic PAH variant in 7 of 1806 proband chromosomes (frequency: 0.0039) from individuals or families with both mild and severe phenylkenoturia (PKU) and phenylalanine hydroxylase deficiency (BâˆšÂ©nit_1999_PMID:10479481; Jeannesson-Thivisol_2015_PMID:26666653; Ho_2014_PMID:24368688; GâˆšÂºttler_1999_PMID:10429004; Desviat_1999_PMID:10234516). The variant was identified in dbSNP (ID: rs62514933) and ClinVar (classified as pathogenic for PKU by Invitae in 2018). The variant was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 4 of 282732 chromosomes at a frequency of 0.000014 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24974 chromosomes (freq: 0.00004) and European (non-Finnish) in 3 of 129052 chromosomes (freq: 0.000023), but not in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The p.Gly218 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. Further, the p.G218V variant was found to have reduced protein stability and accelerated protein degradation (Pey_2003_PMID:12655546). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -

PAH-related disorder

Pathogenic:1

May 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PAH c.653G>T variant is predicted to result in the amino acid substitution p.Gly218Val. This variant has previously been reported, along with a second causative PAH variant, in several patients with phenylalanine hydroxylase deficiency (Guldberg et al. 1993. PubMed ID: 8406445; Bénit et al. 1999. PubMed ID: 10479481; Pey et al. 2003. PubMed ID: 12655546; Jeannesson-Thivisol et al. 2015. PubMed ID: 26666653; Table S3 in Hillert et al. 2020. PubMed ID: 32668217). In functional studies, the p.Gly218Val variant has been shown to decrease the activity of the PAH protein, although the amount of residual enzyme activity reported has varied between studies (Bénit et al. 1999. PubMed ID: 10479481; Pey et al. 2003. PubMed ID: 12655546; Himmelreich et al. 2018. PubMed ID: 30037505). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD. It is interpreted as pathogenic by the ClinGen PAH Variant Curation Expert Panel, and as pathogenic or likely pathogenic by other submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/102773). Based on the collective evidence, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

M;.

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-8.3

D;D

REVEL

Pathogenic

0.93

Sift

Uncertain

0.020

D;D

Sift4G

Benign

0.084

T;T

Polyphen

1.0

D;.

Vest4

0.96

MVP

0.97

MPC

0.26

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.97

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