rs199475661

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000277.3(PAH):c.503del(p.Tyr168SerfsTer27) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000205 in 1,460,604 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. Y168Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PAH
NM_000277.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:5O:1

Conservation

PhyloP100: 5.31

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 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-102866601-GT-G is Pathogenic according to our data. Variant chr12-102866601-GT-G is described in ClinVar as [Pathogenic]. Clinvar id is 102705.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102866601-GT-G 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.503del	p.Tyr168SerfsTer27	frameshift_variant	5/13	ENST00000553106.6
LOC124902999	XR_007063428.1 linkuse as main transcript	n.807+1375del		intron_variant, non_coding_transcript_variant
PAH	NM_001354304.2 linkuse as main transcript	c.503del	p.Tyr168SerfsTer27	frameshift_variant	6/14
PAH	XM_017019370.2 linkuse as main transcript	c.503del	p.Tyr168SerfsTer27	frameshift_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
PAH	ENST00000553106.6 linkuse as main transcript	c.503del	p.Tyr168SerfsTer27	frameshift_variant	5/13	1	NM_000277.3	P1
PAH	ENST00000549111.5 linkuse as main transcript	n.599del		non_coding_transcript_exon_variant	5/6	1
PAH	ENST00000307000.7 linkuse as main transcript	c.488del	p.Tyr163SerfsTer27	frameshift_variant	6/14	5
PAH	ENST00000551988.5 linkuse as main transcript	n.530+10860del		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251346

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135838

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460604

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726692

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:4

Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Aug 10, 2018	PAH-specific ACMG/AMP criteria applied: PVS1: Frameshift variant; PM2: Extremely low frequency. ExAC MAF: 0.00001.; PP4: Detected in PKU patient in international phase II clinical trial for sapropterin. (PMID:23430918). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 22, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 102705). This premature translational stop signal has been observed in individual(s) with hyperphenylalaninemia (PMID: 24368688). This variant is present in population databases (rs199475661, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Tyr168Serfs*27) in the PAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 06, 2016	Variant summary: The PAH c.503delA (p.Tyr168Serfs) variant results in a premature termination codon, predicted to cause a truncated or absent PAH protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.526C>T, p.Arg176X; c.1089delG, p.Lys363fs). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121256 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant has been reported in two unrelated patients who carry c.1222C>T/p.R408W (pathogenic) in trans (Sarkissian_2011 and one internal sample). In addition, one clinical diagnostic laboratory has classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

not provided

Pathogenic:1Other:1

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)	Sep 04, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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