12-102866599-C-G

Variant names:

• chr12-102866599-C-G
• rs199475679
• NM_000277.3:c.506G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP3 PM5 PM2

This summary comes from the ClinGen Evidence Repository: The c.506G>C (p.Arg169Pro) variant in PAH is reported as Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 446524); no further information is provided. At the time of review, the variant does not appear to be reported in the published literature and/or in the BioPKU database. The variant is predicted damaging by multiple lines of computational evidence (PP3). It is absent in gnomAD (PM2). Other missense variants at this site are pathogenic/likely pathogenic – p.Arg169Ser (variant ID 932262), p.Arg169His (variant ID 102706), p.Arg169Gly (variant ID 551103), and p.Arg169Cys (variant ID 125436) (PM5). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386299458/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1
• Conservation: PhyloP100: 2.06
• Publications: 18 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.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.506G>C	p.Arg169Pro	missense_variant	Exon 5 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.506G>C	p.Arg169Pro	missense_variant	Exon 6 of 14		NP_001341233.1
PAH	XM_017019370.2	c.506G>C	p.Arg169Pro	missense_variant	Exon 5 of 7		XP_016874859.1
LOC124902999	XR_007063428.1	n.807+1372C>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.506G>C	p.Arg169Pro	missense_variant	Exon 5 of 13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000549111.5	n.602G>C		non_coding_transcript_exon_variant	Exon 5 of 6	1
PAH	ENST00000307000.7	c.491G>C	p.Arg164Pro	missense_variant	Exon 6 of 14	5		ENSP00000303500.2
PAH	ENST00000551988.5	n.530+10863G>C		intron_variant	Intron 4 of 4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:1 Uncertain:1

Mar 26, 2021

ClinGen PAH Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.506G>C (p.Arg169Pro) variant in PAH is reported as Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 446524); no further information is provided. At the time of review, the variant does not appear to be reported in the published literature and/or in the BioPKU database. The variant is predicted damaging by multiple lines of computational evidence (PP3). It is absent in gnomAD (PM2). Other missense variants at this site are pathogenic/likely pathogenic – p.Arg169Ser (variant ID 932262), p.Arg169His (variant ID 102706), p.Arg169Gly (variant ID 551103), and p.Arg169Cys (variant ID 125436) (PM5). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3. -

Oct 18, 2017

Medical Genetics Center, Academic Academic Center for Education, Culture and Research (ACECR), Khorasan Razavi

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The mutation has been detected in compound heterozygous state with another pathogenic mutation (c.506G>C) in a 5 years old girl affected with PKU and was found in heterozygous in her father. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M;.
PhyloP100		2.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.023	D;D
Polyphen		1.0	D;.
Vest4		0.86
MutPred		0.80		Loss of MoRF binding (P = 0.0059);.;
MVP		0.98
MPC		0.23
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.86
gMVP		0.97
Mutation Taster		=18/82	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs199475679; hg19: chr12-103260377;