rs398123291

Variant names:

• chr12-102894768-GGACAGTGGC-G
• rs398123291
• NM_000277.3:c.310_318delGCCACTGTC

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP4 PM4 PM2

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PM2: Identified a single time in gnomAD (4.06e-06) and absent in ExAC; PM4: p.Ala104_Val106del; PP4: Single patient picked up on NBS with no confirmation studies, no clinical info, no Phe levels, etc. (PMID:27308838). In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PM4, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA220580/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 conservative_inframe_deletion
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2
• Conservation: PhyloP100: 8.30
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• phenylketonuria

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Myriad Women’s Health
• classic phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• maternal phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild hyperphenylalaninemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC124902999 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM4: 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.310_318delGCCACTGTC	p.Ala104_Val106del	conservative_inframe_deletion	Exon 3 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.310_318delGCCACTGTC	p.Ala104_Val106del	conservative_inframe_deletion	Exon 4 of 14		NP_001341233.1
PAH	XM_017019370.2	c.310_318delGCCACTGTC	p.Ala104_Val106del	conservative_inframe_deletion	Exon 3 of 7		XP_016874859.1
LOC124902999	XR_007063428.1	n.863-9929_863-9921delGACAGTGGC		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.310_318delGCCACTGTC	p.Ala104_Val106del	conservative_inframe_deletion	Exon 3 of 13	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251448 AF XY: 0.00

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:1 Uncertain:1

Aug 10, 2018

ClinGen PAH Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

PAH-specific ACMG/AMP criteria applied: PM2: Identified a single time in gnomAD (4.06e-06) and absent in ExAC; PM4: p.Ala104_Val106del; PP4: Single patient picked up on NBS with no confirmation studies, no clinical info, no Phe levels, etc. (PMID:27308838). In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PM4, PP4). -

Oct 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.310_318del, results in the deletion of 3 amino acid(s) of the PAH protein (p.Ala104_Val106del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs398123291, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with PAH-related conditions. ClinVar contains an entry for this variant (Variation ID: 92740). This variant disrupts a region of the PAH protein in which other variant(s) (p.Ala104Asp) have been determined to be pathogenic (PMID: 18299955, 22112818, 22526846, 23764561, 26666653). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Uncertain:1

Sep 29, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.3

Splicing

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

Other links and lift over

dbSNP: rs398123291; hg19: chr12-103288546;