rs62507328

Variant names:

• chr12-102855285-GT-G
• rs62507328
• NM_000277.3:c.556delA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM3_Supporting PVS1 PM2 PP4

This summary comes from the ClinGen Evidence Repository: This c.556del (p.Thr186fs) variant in PAH has been observed in two patients with non-PKU hyperphenylalaninemia, with pathogenic variant p.Arg408Trp, phase unknown (PMID:23357515). This variant is absent from controls in population databases. This is a predicted null frameshift variant in exon 6 out of 13 coding exons. The variant is predicted to undergo nonsense mediated mRNA decay. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_Supporting, and PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229620/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAH NM_000277.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:5 O:1
• Conservation: PhyloP100: 8.02

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: 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	c.556delA	p.Thr186HisfsTer9	frameshift_variant	Exon 6 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.556delA	p.Thr186HisfsTer9	frameshift_variant	Exon 7 of 14		NP_001341233.1
PAH	XM_017019370.2	c.556delA	p.Thr186HisfsTer9	frameshift_variant	Exon 6 of 7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.556delA	p.Thr186HisfsTer9	frameshift_variant	Exon 6 of 13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000549111.5	n.652delA		non_coding_transcript_exon_variant	Exon 6 of 6	1
PAH	ENST00000307000.7	c.541delA	p.Thr181HisfsTer9	frameshift_variant	Exon 7 of 14	5		ENSP00000303500.2
PAH	ENST00000551988.5	n.577delA		non_coding_transcript_exon_variant	Exon 5 of 5	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:5

Aug 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 102733). This premature translational stop signal has been observed in individual(s) with phenylketonuria (PMID: 23357515, 32668217). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr186Hisfs*9) 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). -

Nov 07, 2021

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.556delA (p.Thr186HisfsX9) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant was absent in 251302 control chromosomes. c.556delA has been reported in the literature as a compound heterozygous genotype with other pathogenic PAH alleles in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Reblova_2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories and an expert panel (ClinGen PAH Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (Expert panel)/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 24, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 15, 2020

ClinGen PAH Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

This c.556del (p.Thr186fs) variant in PAH has been observed in two patients with non-PKU hyperphenylalaninemia, with pathogenic variant p.Arg408Trp, phase unknown (PMID: 23357515). This variant is absent from controls in population databases. This is a predicted null frameshift variant in exon 6 out of 13 coding exons. The variant is predicted to undergo nonsense mediated mRNA decay. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_Supporting, and PP4. -

Feb 01, 2018

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Other:1

-

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs62507328; hg19: chr12-103249063;