NM_000277.3(PAH):c.1278T>C (p.Asn426=) AND Phenylketonuria

Germline classification:: Benign (4 submissions)
Last evaluated:: Aug 10, 2018
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000400696.18

Allele description [Variation Report for NM_000277.3(PAH):c.1278T>C (p.Asn426=)]

NM_000277.3(PAH):c.1278T>C (p.Asn426=)

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.1278T>C (p.Asn426=)

Other names:

NM_000277.2(PAH):c.1278T>C

HGVS:

NC_000012.12:g.102840437A>G
NG_008690.2:g.122974T>C
NM_000277.3:c.1278T>CMANE SELECT
NM_001354304.2:c.1278T>C
NP_000268.1:p.Asn426=
NP_001341233.1:p.Asn426=
NC_000012.11:g.103234215A>G
NM_000277.1:c.1278T>C
NP_000268.1:p.(=)

Links:

dbSNP: rs59326968

NCBI 1000 Genomes Browser:

rs59326968

Molecular consequence:

NM_000277.3:c.1278T>C - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354304.2:c.1278T>C - synonymous variant - [Sequence Ontology: SO:0001819]

Condition(s)

Name:: Phenylketonuria (PKU)
Synonyms:: Phenylketonurias; Oligophrenia phenylpyruvica; Folling disease
Identifiers:: MONDO: MONDO:0009861; MedGen: C0031485; Orphanet: 716; OMIM: 261600

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HSCB HscB mitochondrial iron-sulfur cluster cochaperone [Homo sapiens]
HSCB HscB mitochondrial iron-sulfur cluster cochaperone [Homo sapiens]
Gene ID:150274

Gene
150274[uid] AND (alive[prop]) (1)
Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000375559	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Benign (Jan 13, 2018)	germline	clinical testing	Citation Link,
SCV000629178	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Benign (Feb 1, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000852128	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Benign (Aug 10, 2018)	germline	curation	Citation Link,
SCV001458994	Natera, Inc.	no assertion criteria provided	Benign (Sep 16, 2020)	germline	clinical testing

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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, curation

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000375559.3

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

#	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 Invitae, SCV000629178.6

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

#	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 ClinGen PAH Variant Curation Expert Panel, SCV000852128.4

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

Description

PAH-specific ACMG/AMP criteria applied: BA1: MAF=0.16641; BP4: no impact on gene in SIFT, Polyphen2, MutationTaster. In summary this variant meets criteria to be classified as benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BA1, BP4).

#	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 Natera, Inc., SCV001458994.1

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

#	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: Mar 10, 2024

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