VCV002573214.2 - ClinVar

NM_000277.3(PAH):c.229T>C (p.Tyr77His)

Germline

Top reviewed classifications are shown here.

Submission summary:

2 submissions

2 submitters

1 condition

Reviewed by expert panel

Uncertain significance

Mar 2023 by ClinGen PAH Va… FDA Recognized Database

for Phenylketonuria

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000277.3(PAH):c.229T>C (p.Tyr77His)

Variation ID: 2573214 Accession: VCV002573214.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q23.2 12: 102894858 (GRCh38) [ NCBI UCSC ] 12: 103288636 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 29, 2023	Feb 14, 2024	Mar 16, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000277.3:c.229T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000268.1:p.Tyr77His	missense
NM_001354304.2:c.229T>C	NP_001341233.1:p.Tyr77His	missense
NC_000012.12:g.102894858A>G
NC_000012.11:g.103288636A>G
NG_008690.2:g.68553T>C

... more HGVS ... less HGVS

Protein change

Y77H

Other names

NM_001354304.2:c.229T>C

Canonical SPDI

NC_000012.12:102894857:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PAH		-	-	GRCh38 GRCh37	1506	1629

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Phenylketonuria	Uncertain significance (2)	reviewed by expert panel	Mar 16, 2023	RCV003316903.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Mar 16, 2023)	reviewed by expert panel (ClinGen PAH ACMG Specifications v1) Method: curation	Phenylketonuria (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	ClinGen PAH Variant Curation Expert Panel FDA Recognized Database Accession: SCV004015325.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/07f0020e-18ae-45f2-a945-03c89ea141ff Comment: The c.229T>C (p.Tyr77His) variant in PAH is a missense variant predicted to cause substitution of tyrosine by histidine at amino acid 77. It has been … (more) The c.229T>C (p.Tyr77His) variant in PAH is a missense variant predicted to cause substitution of tyrosine by histidine at amino acid 77. It has been detected in 1 patient with mild PKU with second variant not reported (PMID: 27469133). This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant is classified as uncertain significance due to insufficient evidence for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2, PP3, PP4. (less)
Uncertain significance (Jan 14, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004296187.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 27469133 Comment: This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 77 of the PAH protein (p.Tyr77His). … (more) This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 77 of the PAH protein (p.Tyr77His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hyperphenylalaninemia (PMID: 27469133; Invitae). ClinVar contains an entry for this variant (Variation ID: 2573214). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PAH protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)

Comment:

The c.229T>C (p.Tyr77His) variant in PAH is a missense variant predicted to cause substitution of tyrosine by histidine at amino acid 77. It has been detected in 1 patient with mild PKU with second variant not reported (PMID: 27469133). This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant is classified as uncertain significance due to insufficient evidence for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2, PP3, PP4.

Comment:

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 77 of the PAH protein (p.Tyr77His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hyperphenylalaninemia (PMID: 27469133; Invitae). ClinVar contains an entry for this variant (Variation ID: 2573214). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PAH protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The Spectrum of PAH Mutations and Increase of Milder Forms of Phenylketonuria in Sweden During 1965-2014.	Ohlsson A	JIMD reports	2017	PMID: 27469133
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/07f0020e-18ae-45f2-a945-03c89ea141ff	-	-	-	-

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_000277.3(PAH):c.229T>C (p.Tyr77His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...