NM_024996.7(GFM1):c.748C>T (p.Arg250Trp) AND Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Nov 6, 2023
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:: RCV000023564.13

Allele description [Variation Report for NM_024996.7(GFM1):c.748C>T (p.Arg250Trp)]

NM_024996.7(GFM1):c.748C>T (p.Arg250Trp)

Gene:

GFM1:G elongation factor mitochondrial 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3q25.32

Genomic location:

Preferred name:

NM_024996.7(GFM1):c.748C>T (p.Arg250Trp)

HGVS:

NC_000003.12:g.158652154C>T
NG_008441.1:g.12627C>T
NM_001308164.2:c.805C>T
NM_001308166.2:c.748C>T
NM_001374355.1:c.805C>T
NM_001374356.1:c.631C>T
NM_001374357.1:c.523C>T
NM_001374358.1:c.289C>T
NM_001374359.1:c.181C>T
NM_001374360.1:c.181C>T
NM_001374361.1:c.64C>T
NM_024996.7:c.748C>TMANE SELECT
NP_001295093.1:p.Arg269Trp
NP_001295095.1:p.Arg250Trp
NP_001361284.1:p.Arg269Trp
NP_001361285.1:p.Arg211Trp
NP_001361286.1:p.Arg175Trp
NP_001361287.1:p.Arg97Trp
NP_001361288.1:p.Arg61Trp
NP_001361289.1:p.Arg61Trp
NP_001361290.1:p.Arg22Trp
NP_079272.4:p.Arg250Trp
NP_079272.4:p.Arg250Trp
NC_000003.11:g.158369943C>T
NM_024996.5:c.748C>T
NR_164499.1:n.856C>T
NR_164500.1:n.856C>T
NR_164501.1:n.401C>T
NR_164502.1:n.739C>T
Q96RP9:p.Arg250Trp

Protein change:

R175W; ARG250TRP

Links:

UniProtKB: Q96RP9#VAR_076198; OMIM: 606639.0004; dbSNP: rs139430866

NCBI 1000 Genomes Browser:

rs139430866

Molecular consequence:

NM_001308164.2:c.805C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001308166.2:c.748C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374355.1:c.805C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374356.1:c.631C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374357.1:c.523C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374358.1:c.289C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374359.1:c.181C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374360.1:c.181C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374361.1:c.64C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_024996.7:c.748C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_164499.1:n.856C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_164500.1:n.856C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_164501.1:n.401C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_164502.1:n.739C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1
Synonyms:: HEPATOENCEPHALOPATHY, EARLY FATAL PROGRESSIVE; Combined oxidative phosphorylation deficiency 1
Identifiers:: MONDO: MONDO:0012191; MedGen: C1836797; OMIM: 609060

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hypothetical protein FisN_29Hh026 [Fistulifera solaris]
hypothetical protein FisN_29Hh026 [Fistulifera solaris]
gi|1210519469|dbj|GAX21593.1||gnl|W SP|GAX21593

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000044855	OMIM	no assertion criteria provided	Pathogenic (Mar 1, 2011)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000680244	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Nov 8, 2017)	germline	clinical testing	Citation Link,
SCV002081594	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Jan 28, 2021)	germline	clinical testing
SCV004029719	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 26, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28216230, 21119709 Citation Link,
SCV004199288	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 6, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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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
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	2	not provided	not provided	2	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Activation of a cryptic splice site in the mitochondrial elongation factor GFM1 causes combined OXPHOS deficiency.

Simon MT, Ng BG, Friederich MW, Wang RY, Boyer M, Kircher M, Collard R, Buckingham KJ, Chang R, Shendure J, Nickerson DA, Bamshad MJ; University of Washington Center for Mendelian Genomics., Van Hove JLK, Freeze HH, Abdenur JE.

Mitochondrion. 2017 May;34:84-90. doi: 10.1016/j.mito.2017.02.004. Epub 2017 Feb 12.

PubMed [citation]

PMID:: 28216230
PMCID:: PMC5444868

Mutation in subdomain G' of mitochondrial elongation factor G1 is associated with combined OXPHOS deficiency in fibroblasts but not in muscle.

Smits P, Antonicka H, van Hasselt PM, Weraarpachai W, Haller W, Schreurs M, Venselaar H, Rodenburg RJ, Smeitink JA, van den Heuvel LP.

Eur J Hum Genet. 2011 Mar;19(3):275-9. doi: 10.1038/ejhg.2010.208. Epub 2010 Dec 1.

PubMed [citation]

PMID:: 21119709
PMCID:: PMC3062000

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000044855.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a girl, born of consanguineous parents, with combined oxidative phosphorylation deficiency (COXPD1; 609060), Smits et al. (2011) identified a homozygous 748C-T transition in the GFM1 gene, resulting in an arg250-to-trp (R250W) substitution in a highly conserved residue in helix A of the G-prime subdomain, which is part of domain I of the protein. The arg250 residue is positioned on the periphery of the protein and forms a hydrogen bond with glu153; this bond is lost when the trp250 residue is substituted. Immunoblot analysis revealed a severe reduction in the steady-state level of the protein in patient fibroblasts. Patient fibroblasts displayed markedly reduced levels of fully assembled OXPHOS complexes, but the defect was rescued by overexpression of wildtype GFM1. The mutation was not found in 100 controls, and each unaffected parent was heterozygous for the R250W mutation. The patient had a severe, rapidly progressive encephalopathy with axial hypotonia, spasticity, refractory seizures, feeding problems, and increased lactate, and died at age 2 years. Laboratory studies showed decreased enzyme activities of respiratory complexes II, III, and IV in fibroblasts, although muscle biopsy showed low levels only of complex III. However, the capacity of the mitochondrial energy-generating system was reduced in muscle tissue, as indicated by impairments in pyruvate oxidation and ATP production.

#	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

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV000680244.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided
2	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	1	blood	not provided		1	not provided	not provided	not provided
2	germline	yes	1	blood	not provided		1	not provided	not provided	not provided

From Natera, Inc., SCV002081594.1

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004029719.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: GFM1 c.748C>T (p.Arg250Trp) results in a non-conservative amino acid change located in the Translational (tr)-type GTP-binding domain (IPR000795) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251440 control chromosomes in gnomAD. This frequency is not significantly higher than estimated for a pathogenic variant in GFM1 causing Combined Oxidative Phosphorylation Deficiency 1 (4e-05 vs 0.0011), allowing no conclusion about variant significance. c.748C>T has been reported in the literature in individuals affected with features of Combined Oxidative Phosphorylation Deficiency 1, including in trans with another disease-causing variant in at-least two siblings and in the homozygous state in at-least one affected individual (example: Smits_2011, Simon_2017). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in absence of normal GFM1 protein in fibroblasts from patients, which can be rescued by over-expressing normal GFM1 (Smits_2011). The following publications have been ascertained in the context of this evaluation (PMID: 28216230, 21119709). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (pathogenic: n=3; likely pathogenic: n=3). Based on the evidence outlined above, the variant was classified as pathogenic.

#	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 Baylor Genetics, SCV004199288.2

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

Last Updated: Sep 29, 2024

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