NM_024996.7(GFM1):c.748C>T (p.Arg250Trp) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Dec 26, 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:: RCV000800330.7

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]

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
SCV000940038	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 26, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21119709, 28216230, 28492532
SCV003936349	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Jun 27, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000940038

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 26, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV003936349

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Jun 27, 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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

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

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000940038.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 250 of the GFM1 protein (p.Arg250Trp). This variant is present in population databases (rs139430866, gnomAD 0.009%). This missense change has been observed in individual(s) with GFM1-related disease (PMID: 21119709, 28216230). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30598). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GFM1 protein function. For these reasons, this variant has been 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 GeneDx, SCV003936349.1

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

Description

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: 34426522, 21119709, 34277617, 28216230)

#	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: Jun 23, 2024

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