VCV000102602.3 - ClinVar

NM_000277.3(PAH):c.161T>C (p.Leu54Ser)

Germline

Top reviewed classifications are shown here.

Submission summary:

4 submissions

4 submitters

3 conditions

Reviewed by expert panel

Likely pathogenic

Jul 2020 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.161T>C (p.Leu54Ser)

Variation ID: 102602 Accession: VCV000102602.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q23.2 12: 102912798 (GRCh38) [ NCBI UCSC ] 12: 103306576 (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	Mar 19, 2014	Jul 15, 2024	Jul 23, 2020

HGVS

Nucleotide	Protein	Molecular consequence
NM_000277.3:c.161T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000268.1:p.Leu54Ser	missense
NM_001354304.2:c.161T>C	NP_001341233.1:p.Leu54Ser	missense
NC_000012.12:g.102912798A>G
NC_000012.11:g.103306576A>G
NG_008690.2:g.50613T>C

... more HGVS ... less HGVS

Protein change

L54S

Other names

Canonical SPDI

NC_000012.12:102912797: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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

ClinGen: CA229448 dbSNP: rs199475677 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.
not provided	not provided (1)	no classification provided	-	RCV000088843.1
Phenylketonuria	Likely pathogenic (2)	reviewed by expert panel	Jul 23, 2020	RCV000669099.2
not specified	Uncertain significance (1)	criteria provided, single submitter	Apr 19, 2024	RCV004586550.1

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.
Likely pathogenic (Jul 23, 2020)	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: SCV001572856.1 First in ClinVar: May 01, 2021 Last updated: May 01, 2021	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/bfb0df54-1132-4767-9598-0268a4485799 Comment: The c.161T>C (p.Leu54Ser) variant in PAH is a missense variant that is predicted to be deleterious in multiple lines of computational evidence. This variant was … (more) The c.161T>C (p.Leu54Ser) variant in PAH is a missense variant that is predicted to be deleterious in multiple lines of computational evidence. This variant was reported in a Spanish patient with mild/moderate PKU. A defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels and measuring the dihydropteridine reductase activity (PMID: 27121329). This variant was detected in trans with pathogenic variant c.912+1G>A. It was found in extremely low frequency in gnomAD (MAF=0.00006). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4 moderate, PM3, and PP3. (less)
Uncertain significance (Nov 14, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000793804.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (2) PubMed: 27121329‚ 17924342
Uncertain significance (Apr 19, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005077204.1 First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024	Publications: PubMed (2) PubMed: 27121329‚ 32668217 Comment: Variant summary: PAH c.161T>C (p.Leu54Ser) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Four of … (more) Variant summary: PAH c.161T>C (p.Leu54Ser) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251396 control chromosomes. c.161T>C has been reported in the literature as a biallelic compound heterozygous genotye in at-least one individual with moderate Phenylketonuria (PKU) who was also non-responsive on the BH4 loading test (examle, Aldamiz-Echevarria_2016, Hillert_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27121329, 32668217). ClinVar contains an entry for this variant (Variation ID: 102602) with the ClinGen PAH Variant Curation Expert Panel classification as Likely Pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: not provided	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE Accession: SCV000119436.1 First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014

Comment:

The c.161T>C (p.Leu54Ser) variant in PAH is a missense variant that is predicted to be deleterious in multiple lines of computational evidence. This variant was reported in a Spanish patient with mild/moderate PKU. A defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels and measuring the dihydropteridine reductase activity (PMID: 27121329). This variant was detected in trans with pathogenic variant c.912+1G>A. It was found in extremely low frequency in gnomAD (MAF=0.00006). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4 moderate, PM3, and PP3.

Comment:

Variant summary: PAH c.161T>C (p.Leu54Ser) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251396 control chromosomes. c.161T>C has been reported in the literature as a biallelic compound heterozygous genotye in at-least one individual with moderate Phenylketonuria (PKU) who was also non-responsive on the BH4 loading test (examle, Aldamiz-Echevarria_2016, Hillert_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27121329, 32668217). ClinVar contains an entry for this variant (Variation ID: 102602) with the ClinGen PAH Variant Curation Expert Panel classification as Likely Pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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 Genetic Landscape and Epidemiology of Phenylketonuria.	Hillert A	American journal of human genetics	2020	PMID: 32668217
Molecular epidemiology, genotype-phenotype correlation and BH4 responsiveness in Spanish patients with phenylketonuria.	Aldámiz-Echevarría L	Journal of human genetics	2016	PMID: 27121329
Predicted effects of missense mutations on native-state stability account for phenotypic outcome in phenylketonuria, a paradigm of misfolding diseases.	Pey AL	American journal of human genetics	2007	PMID: 17924342
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/bfb0df54-1132-4767-9598-0268a4485799	-	-	-	-

Text-mined citations for rs199475677 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jul 23, 2024

ClinVar Genomic variation as it relates to human health

NM_000277.3(PAH):c.161T>C (p.Leu54Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs199475677 ...