NM_000277.3(PAH):c.963C>T (p.Leu321=) AND not specified

Germline classification:: Benign (3 submissions)
Last evaluated:: Jun 17, 2019
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000507684.4

Allele description [Variation Report for NM_000277.3(PAH):c.963C>T (p.Leu321=)]

NM_000277.3(PAH):c.963C>T (p.Leu321=)

Gene:

PAH:phenylalanine hydroxylase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q23.2

Genomic location:

Preferred name:

NM_000277.3(PAH):c.963C>T (p.Leu321=)

Other names:

NM_000277.2(PAH):c.963C>T

HGVS:

NC_000012.12:g.102846901G>A
NG_008690.2:g.116510C>T
NM_000277.3:c.963C>TMANE SELECT
NM_001354304.2:c.963C>T
NP_000268.1:p.Leu321=
NP_001341233.1:p.Leu321=
NC_000012.11:g.103240679G>A
NM_000277.1:c.963C>T
p.=

Links:

dbSNP: rs61747292

NCBI 1000 Genomes Browser:

rs61747292

Molecular consequence:

NM_000277.3:c.963C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354304.2:c.963C>T - synonymous variant - [Sequence Ontology: SO:0001819]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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cytochrome c oxidase subunit 1, partial (mitochondrion) [Planiliza sp. 34r]
cytochrome c oxidase subunit 1, partial (mitochondrion) [Planiliza sp. 34r]
gi|1778565904|gb|QGP73511.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000601720	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Benign (Oct 12, 2016)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 12210276, 11139255, 18590700, 12644360, 23856132, 18937293, 16402341, 26467025
SCV000729359	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Benign (Feb 27, 2018)	germline	clinical testing	Citation Link,
SCV001361062	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Jun 17, 2019)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000601720

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Benign
(Oct 12, 2016)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV000729359

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Benign
(Feb 27, 2018)

germline

clinical testing

Citation Link,

SCV001361062

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Benign
(Jun 17, 2019)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Aromatic amino acid hydroxylase genes and schizophrenia.

Chao HM, Richardson MA.

Am J Med Genet. 2002 Aug 8;114(6):626-30.

PubMed [citation]

PMID:: 12210276

Ten novel mutations in the phenylalanine hydroxylase gene (PAH) observed in Brazilian patients with phenylketonuria.

Acosta AX, Silva WA Jr, Carvalho TM, Zago MA.

Hum Mutat. 2001;17(1):77.

PubMed [citation]

PMID:: 11139255

See all PubMed Citations (8)

Details of each submission

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000601720.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV000729359.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001361062.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Variant summary: PAH c.963C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0039 in 251262 control chromosomes, predominantly at a frequency of 0.053 within the African or African-American subpopulation in the gnomAD database, including 26 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 7-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) phenotype (0.0079), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Three ClinVar submissions from clinical diagnostic laboratories and an expert panel (ClinGen)(evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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