rs62516097

chr12-102843738-CAGCTCCAGGGGGAGA-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM4 PP3 PP5_Very_Strong

The NM_000277.3(PAH):c.1092_1106del(p.Leu365_Leu369del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. L364L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PAH NM_000277.3 inframe_deletion
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 O:1
• Conservation: PhyloP100: 9.32

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 13 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000277.3
• PM4: Nonframeshift variant in NON repetitive region in NM_000277.3.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 12-102843738-CAGCTCCAGGGGGAGA-C is Pathogenic according to our data. Variant chr12-102843738-CAGCTCCAGGGGGAGA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 620.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102843738-CAGCTCCAGGGGGAGA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.1092_1106del	p.Leu365_Leu369del	inframe_deletion	11/13	ENST00000553106.6
PAH	NM_001354304.2	c.1092_1106del	p.Leu365_Leu369del	inframe_deletion	12/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.1092_1106del	p.Leu365_Leu369del	inframe_deletion	11/13	1	NM_000277.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1992	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	May 04, 2019	The c.1092_1106del (p.Leu365_Leu369del) variant in PAH has been reported in 1 individual with PKU (PP4; PMID: 1363837) in trans with pathogenic variant p.R408W (PM3). This variant is absent in population databases (PM2). This variant is a 15 bp in-frame deletion in exon 11 (PM4). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3, PM4. -

not provided Other:1

not provided, no classification provided

literature only

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs62516097; hg19: chr12-103237516;