rs62508727

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong

The NM_000277.3(PAH):c.284_286del(p.Ile95del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. I95I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

PAH
NM_000277.3 inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:12O:2

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 Pathogenic. Variant got 13 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000277.3

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_000277.3. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 12-102894800-TTGA-T is Pathogenic according to our data. Variant chr12-102894800-TTGA-T is described in ClinVar as [Pathogenic]. Clinvar id is 604.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102894800-TTGA-T is described in Lovd as [Pathogenic]. Variant chr12-102894800-TTGA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PAH	NM_000277.3 linkuse as main transcript	c.284_286del	p.Ile95del	inframe_deletion	3/13	ENST00000553106.6
LOC124902999	XR_007063428.1 linkuse as main transcript	n.863-9892_863-9890del		intron_variant, non_coding_transcript_variant
PAH	NM_001354304.2 linkuse as main transcript	c.284_286del	p.Ile95del	inframe_deletion	4/14
PAH	XM_017019370.2 linkuse as main transcript	c.284_286del	p.Ile95del	inframe_deletion	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.284_286del	p.Ile95del	inframe_deletion	3/13	1	NM_000277.3	P1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0000655

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251448

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000239

AC:

AN:

1461828

Hom.:

AF XY:

0.0000289

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000125

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000208

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:9

Pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	The PAH c.284_286delTCA (p.I95del) variant results in a deletion of a single amino acid and has been observed in homozygous and compound heterozygous state in individuals with phenylketonuria. This variant has previously been shown to result in a reduced affinity of the PAH enzyme for phenylalanine (PMID: 1709636; 18985011; 19292873; 25894915; 26666653). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 19, 2023	- -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Oct 18, 2019	This variant was documented in 8 patients diagnosed with PAH deficiency (PMID: 26503515, 30747360, 30050108, 29560316, 18985011). Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis, and DHPR activity assay. This variant was detected in trans with a pathogenic or likely pathogenic PAH variant in 2 patients with PKU and 3 patients with hyperphenylalaninemia (PMID: 19292873, 24368688, 25894915, 26666653, 29316886). This variant is present at a frequency below 0.0002 in the population databases ExAC and gnomAD. This variant changes protein length from an in-frame deletion in a non-repeat region. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM4, PP4_moderate. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 15, 2007	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 06, 2023	The p.Ile95del variant in PAH has been reported, in the homozygous and compound heterozygous state, in numerous (at least 10) individuals with PAH deficiency (phenylketonuria or hyperphenylalaninemia) (Li 2015 PMID: 26503515, Yan 2019 PMID: 30747360, Li 2008 PMID: 30050108, Schwoerer 2018 PMID: 29560316, Lee 2008 PMID: 18985011, Daniele 2009 PMID: 19292873, Ho 2014 PMID: 24368688, Chen 2015 PMID: 25894915, Jeannesson-Thivisol 2015 PMID: 26666653, Liu 2018 PMID: 29316886). It has also been classified as pathogenic on Oct 18, 2019 by the ClinGen PAH Variant Curation Expert Panel (Variation ID 604) and has been identified in 13/912 Amish and 5/68036 European chromosomes by gnomAD (https://gnomad.broadinstitute.org/). This variant is a deletion of 1 amino acid at position 95 and is not predicted to alter the protein reading-frame. In vitro functional studies support an impact on protein function as they show it results in a reduced affinity of the PAH enzyme for phenylalanine (Caillaud 1991 PMID: 1709636). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive phenylalanine hydroxylase (PAH) deficiency. ACMG/AMP criteria applied: PM3_Very strong, PM2_Supporting, PM4, PS3_Moderate. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 15, 2020	Variant summary: PAH c.284_286delTCA (p.Ile95del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 2e-05 in 251448 control chromosomes. c.284_286delTCA has been well reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Chien_2004, Daniele_2007, Caillaud_1991). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal enzyme activity (Maximal velocity/Km) due to a markedly decreased subtrate specificity (increased Km) for Phenylalanine (Caillaud_1991). Five 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 (n=4)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	This variant, c.284_286del, results in the deletion of 1 amino acid(s) of the PAH protein (p.Ile95del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs62508727, gnomAD 0.006%). This variant has been observed in individual(s) with phenylketonuria and hyperphenylalaninemia (PMID: 1709636, 14722928, 17096675, 18985011, 19292873, 23430918, 25894915, 26666653). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Ile94del. ClinVar contains an entry for this variant (Variation ID: 604). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	May 19, 2016	- -

not provided

Pathogenic:3Other:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2020	In-frame deletion of 1 amino acid in a non-repeat region predicted to critically alter the protein; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports a deleterious effect on protein structure/function; Responsiveness to BH4 therapy is inconsistent (Zurfluh et al., 2008; Jeannesson-Thivisol et al., 2015); This variant is associated with the following publications: (PMID: 25894915, 19292873, 25255367, 14722928, 1709636, 17935162, 26503515, 24705691, 26666653, 19194782, 18985011, 17096675, 16256386, 24368688, 23430918, 20217238, 30487145, 31028937, 30747360, 32668217, 31589614, 32853555) -
not provided, flagged submission	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 07, 2017	- -
not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 06, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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