12-102866600-G-C

Variant names:

• chr12-102866600-G-C
• rs281865440
• NM_000277.3:c.505C>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP3 PM5 PM3_Strong PP4_Moderate PM2

This summary comes from the ClinGen Evidence Repository: The variant c.505C>G (p.R169G) in PAH has been detected in 2 Chinese patients and 1 Dutch patient with Phe levels >120 umol/l (PMID 26503515, 30050108, 31924462) (PP4-Moderate). This variant was detected in trans with pathogenic variants p.R243Q, p.R241Pfs*100; the validation tests on parents were performed using Sanger sequencing. Also found with pathogenic variant p.Y414C; parental testing not confirmed (PMID:30050108, 31924462) (PM3-Strong). This variant is absent from controls in gnomAD, 1000 Genomes or ESP (PM2). Multiple lines of computational evidence support a deleterious effect: SIFT, PolyPhen2, and MutationTaster. REVEL score =0.848 (PP4). Missesense variant p.Arg169Ser interpreted as pathogenic by ClinGen PAH VCEP, located at the same amino acid residue (PM5). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4-Moderate, PM3-Strong, PP3, PM5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16020804/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:1 U:1
• Conservation: PhyloP100: 1.07
• Publications: 5 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: Pathogenic. The variant received 11 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: 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.
• 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.505C>G	p.Arg169Gly	missense_variant	Exon 5 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.505C>G	p.Arg169Gly	missense_variant	Exon 6 of 14		NP_001341233.1
PAH	XM_017019370.2	c.505C>G	p.Arg169Gly	missense_variant	Exon 5 of 7		XP_016874859.1
LOC124902999	XR_007063428.1	n.807+1373G>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.505C>G	p.Arg169Gly	missense_variant	Exon 5 of 13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000549111.5	n.601C>G		non_coding_transcript_exon_variant	Exon 5 of 6	1
PAH	ENST00000307000.7	c.490C>G	p.Arg164Gly	missense_variant	Exon 6 of 14	5		ENSP00000303500.2
PAH	ENST00000551988.5	n.530+10862C>G		intron_variant	Intron 4 of 4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:1 Uncertain:1

Feb 12, 2021

ClinGen PAH Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The variant c.505C>G (p.R169G) in PAH has been detected in 2 Chinese patients and 1 Dutch patient with Phe levels >120 umol/l (PMID 26503515, 30050108, 31924462) (PP4-Moderate). This variant was detected in trans with pathogenic variants p.R243Q, p.R241Pfs*100; the validation tests on parents were performed using Sanger sequencing. Also found with pathogenic variant p.Y414C; parental testing not confirmed (PMID: 30050108, 31924462) (PM3-Strong). This variant is absent from controls in gnomAD, 1000 Genomes or ESP (PM2). Multiple lines of computational evidence support a deleterious effect: SIFT, PolyPhen2, and MutationTaster. REVEL score =0.848 (PP4). Missesense variant p.Arg169Ser interpreted as pathogenic by ClinGen PAH VCEP, located at the same amino acid residue (PM5). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4-Moderate, PM3-Strong, PP3, PM5. -

Mar 10, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.82	T;T
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;.
PhyloP100		1.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.98	D;.
Vest4		0.88
MutPred		0.81		Loss of MoRF binding (P = 0.0202);.;
MVP		0.96
MPC		0.14
ClinPred		1.0	D
GERP RS		-0.060
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.86
gMVP		0.93
Mutation Taster		=3/97	disease causing

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: rs281865440; hg19: chr12-103260378;