dbSNP rs762462102: PAH:p.Phe39del (chr12-102912840-GAGA-G) – ACMG Classification: Pathogenic (13 pts)

Variant summary

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

The NM_000277.3(PAH):c.116_118delTCT(p.Phe39del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000821 in 1,461,348 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

PAH
NM_000277.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:12O:1

Conservation

PhyloP100: 5.97

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a strand (size 7) in uniprot entity PH4H_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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 12-102912840-GAGA-G is Pathogenic according to our data. Variant chr12-102912840-GAGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 188933.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102912840-GAGA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3 link	c.116_118delTCT	p.Phe39del	disruptive_inframe_deletion	Exon 2 of 13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.116_118delTCT	p.Phe39del	disruptive_inframe_deletion	Exon 3 of 14		NP_001341233.1
PAH	XM_017019370.2 link	c.116_118delTCT	p.Phe39del	disruptive_inframe_deletion	Exon 2 of 7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 link	c.116_118delTCT	p.Phe39del	disruptive_inframe_deletion	Exon 2 of 13	1	NM_000277.3	ENSP00000448059.1		P00439

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251412

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135874

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461348

Hom.:

AF XY:

0.00000825

AC XY:

AN XY:

726990

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:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:9

Dec 30, 2023

ClinGen PAH Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

This c.113_115TCTdel (p.Phe39del) variant is also known as c.115_117delTTC (p.Phe39del) in the literature. This variant in PAH was reported in 3 Chinese patients with PAH deficiency (PMID: 26503515). DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia. This variant was documented in 5 patients with PAH deficiency with a pathogenic or likely pathogenic variant in trans (PMID: 16256386, 23500595, 26542770, 29102225, 12655550). This variant is present in European (non-Finnish) populations at a frequency of 0.000035 (gnomAD), and in European (non-Finnish) populations at a frequency of 0.000045 (ExAC). This variant changes the protein length from an in-frame deletion in a non-repetitive region. Functional analysis of this variant found that it is associated with approximately 20% residual enzyme activity (PMID: 11161839; 17935162). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2_supporting, PP4_moderate, PM4, PS3-supporting, PM3_strong. -

Jul 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.116_118del, results in the deletion of 1 amino acid(s) of the PAH protein (p.Phe39del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs762462102, gnomAD 0.004%). This variant has been observed in individual(s) with phenylketonuria (PMID: 9452062, 12655550, 16256386, 19394257, 23500595, 26210745, 26542770). This variant is also known as DF39. ClinVar contains an entry for this variant (Variation ID: 188933). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts the p.Phe39 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 206386, 8592329, 8659548, 12655544, 12655553, 17935162). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Oct 01, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 07, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 23, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 22, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Feb 22, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 23, 2018

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.116_118delTCT (p.Phe39del) results in an in-frame deletion that is predicted to remove a Phe amino acid from the encoded protein. The variant allele was found at a frequency of 1.6e-05 in 246172 control chromosomes. c.116_118delTCT has been reported in the literature in multiple individuals affected with classic and mild Phenylalanine Hydroxylase Deficiency (Phenylketonuria) and mild hyperphenylalaninemia (Aldamiz-Echevarria_2016 and Zurfluh_2008). The variant was indicated to have 20% PAH enzyme activity (Zurfluh_2008). These data indicate that the variant is very likely to be associated with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:3Other:1

Oct 30, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 13, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect on enzyme activity (Gjetting et al., 2001; Zurfluh et al, 2008); In-frame deletion of 1 amino acid in a non-repeat region predicted to critically alter the protein; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27121329, 26503515, 23430918, 34828281, 23500595, 17935162, 8406445, 18294361, 21147011, 28676969, 29499199, 34440436, 31589614, 32668217, 28182360, 35405047, 36246604, 11161839) -

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PAH: PS4, PM2, PM3, PM4, PP4, PS3:Supporting -

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