rs199475659

Variant names:

• chr12-102840414-G-A
• rs199475659
• NM_000277.3:c.1301C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-102840414-G-A
• chr12-102840414-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP4 PM5 PM3_Supporting PM2

This summary comes from the ClinGen Evidence Repository: The c.1301C>T (p.Ala434Val) variant in PAH has been reported in 1 individual with classic PKU detected with pathogenic variant p.R243X (PMID:24350308). This variant is absent in population databases. Another missense change at the same amino acid (p.Ala434Asp) is likely pathogenic by 1 submitter and pathogenic by PAH VCEP. Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PM3_supporting, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16020990/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: 9.46
• 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), ClinGen, Myriad Women’s Health, G2P
• 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.
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	NM_000277.3	MANE Select	c.1301C>T	p.Ala434Val	missense	Exon 12 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.1301C>T	p.Ala434Val	missense	Exon 13 of 14	NP_001341233.1	P00439

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	ENST00000553106.6	TSL:1 MANE Select	c.1301C>T	p.Ala434Val	missense	Exon 12 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000906695.1		c.1400C>T	p.Ala467Val	missense	Exon 13 of 14	ENSP00000576754.1
	PAH	ENST00000906692.1		c.1379C>T	p.Ala460Val	missense	Exon 12 of 13	ENSP00000576751.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

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	Benign	0.23
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Benign	23
DANN	Benign	0.39
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.18	N
PhyloP100		9.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.52	N
REVEL	Pathogenic	0.87
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.83	P
Vest4		0.78
MutPred		0.53		Loss of ubiquitination at K431 (P = 0.1016)
MVP		0.96
MPC		0.048
ClinPred		0.82	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.78
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs199475659; hg19: chr12-103234192;