NM_001395413.1(POR):c.1361G>A (p.Arg454His) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 17, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003150931.10

Allele description [Variation Report for NM_001395413.1(POR):c.1361G>A (p.Arg454His)]

NM_001395413.1(POR):c.1361G>A (p.Arg454His)

Gene:

POR:cytochrome p450 oxidoreductase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q11.23

Genomic location:

Preferred name:

NM_001395413.1(POR):c.1361G>A (p.Arg454His)

Other names:

R457H

HGVS:

NC_000007.14:g.75985179G>A
NG_008930.1:g.75078G>A
NM_001367562.3:c.1361G>A
NM_001382655.3:c.1415G>A
NM_001382657.2:c.1361G>A
NM_001382658.3:c.1361G>A
NM_001382659.3:c.1361G>A
NM_001382662.3:c.1239+221G>A
NM_001395413.1:c.1361G>AMANE SELECT
NP_001354491.2:p.Arg454His
NP_001369584.2:p.Arg472His
NP_001369586.2:p.Arg454His
NP_001369587.2:p.Arg454His
NP_001369588.2:p.Arg454His
NP_001382342.1:p.Arg454His
NC_000007.13:g.75614497G>A
NM_000941.2:c.1370G>A

Protein change:

R454H; ARG457HIS

Links:

OMIM: 124015.0005; dbSNP: rs28931608

NCBI 1000 Genomes Browser:

rs28931608

Molecular consequence:

NM_001382662.3:c.1239+221G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001367562.3:c.1361G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001382655.3:c.1415G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001382657.2:c.1361G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001382658.3:c.1361G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001382659.3:c.1361G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001395413.1:c.1361G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV003839908	Genetic Services Laboratory, University of Chicago	no assertion criteria provided	Pathogenic (Aug 15, 2022)	germline	clinical testing
SCV004014196	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jul 17, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003839908

Genetic Services Laboratory, University of Chicago

no assertion criteria provided

Pathogenic
(Aug 15, 2022)

germline

clinical testing

SCV004014196

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jul 17, 2023)

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV003839908.1

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

Description

This sequence change, c.1370G>A, is in exon 12 results and in an amino acid change, p.Arg457His. The p.Arg457His change affects a highly conserved amino acid residue located in a domain of the POR protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, Align GVGD, REVEL) provide contradictory results for the p.Arg457His substitution. This sequence change has previously been described in several patients with cytochrome P450 oxidoreductase deficiency (POR) deficiency with or without Antley-Bixler syndrome and is considered a founder mutation in the Japanese population (PMID: 15483095, 16470797, 14758361, 19258400). This sequence change has been described in the gnomAD database with a frequency of 0.05% in the East Asian subpopulation (dbSNP rs28931608). These collective evidences indicate that this sequence change is pathogenic.

#	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 GeneDx, SCV004014196.1

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

Description

Published functional studies demonstrate a damaging effect resulting in reduced enzyme activity (Flck et al., 2004); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21741353, 20732302, 20940534, 20124576, 20697309, 32820517, 16495354, 17062779, 22252407, 22123124, 17635179, 22162478, 18551037, 22547083, 21808038, 16470797, 28288674, 16439592, 18853185, 28841001, 29289577, 31299979, 31754721, 33336784, 29944250, 32973886, 35070845, 19258400, 14758361)

#	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

Last Updated: Nov 24, 2024

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