rs62508727

Positions:

• chr12-102894800-TTGA-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_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 (★★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: PAH NM_000277.3 inframe_deletion
• Clinical Significance: Pathogenic reviewed by expert panel P:13 O:2
• Conservation: PhyloP100: 8.30

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]

LOC124902999 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• 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	Protein	UniProt
PAH	NM_000277.3	c.284_286del	p.Ile95del	inframe_deletion	3/13	ENST00000553106.6	NP_000268.1
LOC124902999	XR_007063428.1	n.863-9892_863-9890del		intron_variant, non_coding_transcript_variant
PAH	NM_001354304.2	c.284_286del	p.Ile95del	inframe_deletion	4/14		NP_001341233.1
PAH	XM_017019370.2	c.284_286del	p.Ile95del	inframe_deletion	3/7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.284_286del	p.Ile95del	inframe_deletion	3/13	1	NM_000277.3	ENSP00000448059	P1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152190 Hom.: 0 Cov.: 32

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: 5 AN: 251448 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135894

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: 35 AN: 1461828 Hom.: 0 AF XY: 0.0000289 AC XY: 21 AN XY: 727216

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: 19 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74360

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:13 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -
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, 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, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 16, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 15, 2007	- -
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	Neuberg Centre For Genomic Medicine, NCGM	-	The observed inframe deletion variant c.284_286del (p.Ile95del) in PAH gene as been reported previously in multiple individuals affected with phenylketonuria (Schwoerer et al. 2018; Yan et al. 2019). In vitro expression studies showed that this variant produced very low levels of PAH activity (Caillaud et al. 1991; Li et al. 2015). The p.Ile95del variant is present with an allele frequency of 0.002% in the gnomAD exomes database. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). This p.Ile95del causes deletion of amino acid Isoleucine at position 95. For these reasons, this variant has been classified as Pathogenic. -
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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	May 19, 2016	- -

not provided Pathogenic:3 Other:2

not provided, flagged submission	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 06, 2013	- -
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	-	- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs62508727; hg19: chr12-103288578;