NM_000277.3(PAH):c.1139C>T (p.Thr380Met) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Conflicting interpretations of pathogenicity (7 submissions)
Last evaluated:: Nov 3, 2021
Review status:: criteria provided, conflicting classifications

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:: RCV000078502.45

Allele description

NM_000277.3(PAH):c.1139C>T (p.Thr380Met)

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.1139C>T (p.Thr380Met)

Other names:

p.T380M:ACG>ATG; NM_000277.1(PAH):c.1139C>T

HGVS:

NC_000012.12:g.102843706G>A
NG_008690.2:g.119705C>T
NM_000277.3:c.1139C>TMANE SELECT
NM_001354304.2:c.1139C>T
NP_000268.1:p.Thr380Met
NP_000268.1:p.Thr380Met
NP_001341233.1:p.Thr380Met
NC_000012.11:g.103237484G>A
NM_000277.1:c.1139C>T
P00439:p.Thr380Met

Protein change:

T380M; THR380MET

Links:

UniProtKB: P00439#VAR_001022; OMIM: 612349.0054; dbSNP: rs62642937

NCBI 1000 Genomes Browser:

rs62642937

Molecular consequence:

NM_000277.3:c.1139C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.1139C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000110358	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Aug 8, 2016)	germline	clinical testing	Citation Link,
SCV000119353	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	no classification provided	not provided	not provided	not provided
SCV000239086	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Dec 30, 2019)	germline	clinical testing	Citation Link,
SCV000601707	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Jun 14, 2021)	unknown	clinical testing	PubMed (16) [See all records that cite these PMIDs] 32906206, 33803550, 8268925, 23500595, 25333069, 22698810, 25087612, 7981714, 8533759, 26600521, 10234516, 18294361, 21307867, 27620137, 27121329, 26467025
SCV001501014	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Jan 1, 2021)	germline	clinical testing	Citation Link,
SCV001958930	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely pathogenic	germline	clinical testing
SCV002009280	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 3, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	9	not provided	not provided	not provided	not provided	clinical testing
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Frequency spectrum of rare and clinically relevant markers in multiethnic Indian populations (ClinIndb): A resource for genomic medicine in India.

Narang A, Uppilli B, Vivekanand A, Naushin S, Yadav A, Singhal K, Shamim U, Sharma P, Zahra S, Mathur A, Seth M, Parveen S, Vats A, Hillman S, Dolma P, Varma B, Jain V; TRISUTRA Ayurgenomics Consortium., Prasher B, Sengupta S, Mukerji M, Faruq M.

Hum Mutat. 2020 Nov;41(11):1833-1847. doi: 10.1002/humu.24102. Epub 2020 Sep 9.

PubMed [citation]

PMID:: 32906206

Clinical and Genetic Characteristics of Patients with Mild Hyperphenylalaninemia Identified by Newborn Screening Program in Japan.

Odagiri S, Kabata D, Tomita S, Kudo S, Sakaguchi T, Nakano N, Yamamoto K, Shintaku H, Hamazaki T.

Int J Neonatal Screen. 2021 Mar 18;7(1). doi:pii: 17. 10.3390/ijns7010017.

PubMed [citation]

PMID:: 33803550
PMCID:: PMC8006226

See all PubMed Citations (17)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000110358.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	9	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		9	not provided	not provided	not provided

From DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE, SCV000119353.1

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

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

From GeneDx, SCV000239086.13

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

Description

Functional analysis demonstrates that T380M is associated with 38% of wildtype PAH enzyme activity (Heintz et al., 2012); This variant is associated with the following publications: (PMID: 26990548, 23500595, 23792259, 31355225, 12655544, 17935162, 25087612, 25333069, 8268925, 27620137, 22698810, 30337205, 30747360, 29731766, 31980526, 30275481, 31589614, 32668217)

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000601707.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

This variant is associated with mild hyperphenylalaninemia when present with any other disease-causing variant in the PAH gene (PMIDs: 7981714 (1994), 8533759 (1995), 8268925 (1993), 18294361 (2008), 23500595 (2013), 26600521 (2015), 27121329 (2016), 33803550 (2021)), and is present in a significant percentage of individuals with PAH deficiency (PMIDs: 10234516 (1999), 21307867 (2011), and 27121329 (2016)). Additionally, multiple functional studies have indicated this variant has reduced activity compared to wild type and may affect splicing (PMIDs: 22698810 (2012) and 27620137 (2016)).

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

From CeGaT Center for Human Genetics Tuebingen, SCV001501014.22

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

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001958930.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV002009280.3

#	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	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

Relating variation to medicine