NM_005262.3(GFER):c.581G>A (p.Arg194His) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jul 31, 2024
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:: RCV000199876.11

Allele description [Variation Report for NM_005262.3(GFER):c.581G>A (p.Arg194His)]

NM_005262.3(GFER):c.581G>A (p.Arg194His)

Gene:

GFER:growth factor, augmenter of liver regeneration [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_005262.3(GFER):c.581G>A (p.Arg194His)

Other names:

p.R194H:CGC>CAC

HGVS:

NC_000016.10:g.1985991G>A
NG_016288.1:g.6843G>A
NM_005262.3:c.581G>AMANE SELECT
NP_005253.3:p.Arg194His
NC_000016.9:g.2035992G>A
NM_005262.2:c.581G>A
P55789:p.Arg194His

Protein change:

R194H; ARG194HIS

Links:

UniProtKB: P55789#VAR_063435; UniProtKB/Swiss-Prot: VAR_063435; OMIM: 600924.0001; dbSNP: rs121908192

NCBI 1000 Genomes Browser:

rs121908192

Molecular consequence:

NM_005262.3:c.581G>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
SCV000251537	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jul 31, 2024)	germline	clinical testing	Citation Link,
SCV000802112	Mayo Clinic Laboratories, Mayo Clinic	no assertion criteria provided	Pathogenic (Mar 8, 2016)	unknown	clinical testing
SCV003292684	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 24, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25269795, 19409522, 26018198, 26944241, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000251537

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jul 31, 2024)

germline

clinical testing

Citation Link,

SCV000802112

Mayo Clinic Laboratories, Mayo Clinic

no assertion criteria provided

Pathogenic
(Mar 8, 2016)

unknown

clinical testing

SCV003292684

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 24, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

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
not provided	germline	unknown	not provided	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

The disease-associated mutation of the mitochondrial thiol oxidase Erv1 impairs cofactor binding during its catalytic reaction.

Ceh-Pavia E, Ang SK, Spiller MP, Lu H.

Biochem J. 2014 Dec 15;464(3):449-59. doi: 10.1042/BJ20140679.

PubMed [citation]

PMID:: 25269795

The mitochondrial disulfide relay system protein GFER is mutated in autosomal-recessive myopathy with cataract and combined respiratory-chain deficiency.

Di Fonzo A, Ronchi D, Lodi T, Fassone E, Tigano M, Lamperti C, Corti S, Bordoni A, Fortunato F, Nizzardo M, Napoli L, Donadoni C, Salani S, Saladino F, Moggio M, Bresolin N, Ferrero I, Comi GP.

Am J Hum Genet. 2009 May;84(5):594-604. doi: 10.1016/j.ajhg.2009.04.004. Epub 2009 Apr 30.

PubMed [citation]

PMID:: 19409522
PMCID:: PMC2681006

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000251537.14

#	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 suggest a damaging effect (protein instability and altered localization) (PMID: 20593814, 19409522); Not observed at significant frequency in large population cohorts (gnomAD); 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: 25269795, 26018198, 33144682, 19409522, 26944241, 34758253, 20593814, 28155230)

#	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 Mayo Clinic Laboratories, Mayo Clinic, SCV000802112.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003292684.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GFER function (PMID: 19409522, 25269795). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 8691). This missense change has been observed in individuals with mitochondrial myopathy (PMID: 19409522, 26018198, 26944241). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121908192, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 194 of the GFER protein (p.Arg194His).

#	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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