rs62514959

Variant names:

• chr12-102844424-C-G
• rs62514959
• NM_000277.3:c.977G>C

Your query was ambiguous. Multiple possible variants found:

• chr12-102844424-C-G
• chr12-102844424-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP4 PM2_Supporting PM3_Supporting PP3_Moderate PM5_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000277.3(PAH):c.977G>C (p.Trp326Ser) variant is a missense variant in exon 10/13 of PAH. This variant has been previously reported in at least one proband with hyperphenylalanemia (HPA; Palmieri, A. (2013). MOLECULAR ANALYSIS OF PHENYLALANINE HYDROXYLASE GENE IN SOUTH ITALY PATIENTS AFFECTED BY PHENYLKETONURIA) in whom BH4 deficiency was not formally excluded by normal urine pterins and normal DHPR activity, or sequencing of genes in the BH4 cofactor metabolism pathway to exclude a defect of BH4 cofactor metabolism (PP4_Supporting). This variant has been reported in at least one proband with the genotype p.Leu48Ser/p.Trp326Ser (phase not confirmed) phenotype (PMID:32668217); the p.Leu48Ser variant is path in ClinVar by PAH VCEP (Var ID: 608) (PM3_Supporting). The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.874) (PP3_Moderate). A different missense variant at the same site, p.Trp326Cys, has been previously reported in one patient with HPA (PMID:36537053), BH4 deficiency not excluded, in presumed trans w/p.R408W (path by PAH VCEP, ClinVar ID 577); the p.W326C variant qualifies as likely path (PM3_Supp, PP3_Mod, PP4_Mod (hyperphenylalanemia, BH4 deficiency excluded by sequencing of genes in sequencing of genes in the BH4 cofactor metabolism pathway, PM2_Supp), such that PM5_Supporting is met. In summary, this variant meets criteria to be classified as Likely Pathogenic based on the ACMG/AMP criteria applied, as specified by the ClinGen Phenylketonuria Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting, PM3_Supporting, PM5_Supporting, PP4_Supporting, PP3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16020913/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: 6.06
• 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000277.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	NM_000277.3	MANE Select	c.977G>C	p.Trp326Ser	missense	Exon 10 of 13	NP_000268.1
	PAH	NM_001354304.2		c.977G>C	p.Trp326Ser	missense	Exon 11 of 14	NP_001341233.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	ENST00000553106.6	TSL:1 MANE Select	c.977G>C	p.Trp326Ser	missense	Exon 10 of 13	ENSP00000448059.1
	PAH	ENST00000307000.7	TSL:5	c.962G>C	p.Trp321Ser	missense	Exon 11 of 14	ENSP00000303500.2
	PAH	ENST00000635477.1	TSL:5	c.80G>C	p.Trp27Ser	missense	Exon 3 of 6	ENSP00000489230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Phenylketonuria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.8	H
PhyloP100		6.1
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-13	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.88		Loss of stability (P = 0.1278)
MVP		1.0
MPC		0.28
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.99
Mutation Taster		=0/100	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: rs62514959; hg19: chr12-103238202;