NM_000144.5(FXN):c.389G>T (p.Gly130Val) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Mar 21, 2024
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:: RCV000992016.10

Allele description [Variation Report for NM_000144.5(FXN):c.389G>T (p.Gly130Val)]

NM_000144.5(FXN):c.389G>T (p.Gly130Val)

Gene:

FXN:frataxin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q21.11

Genomic location:

Preferred name:

NM_000144.5(FXN):c.389G>T (p.Gly130Val)

HGVS:

NC_000009.12:g.69064942G>T
NG_008845.2:g.34380G>T
NM_000144.5:c.389G>TMANE SELECT
NM_181425.3:c.389G>T
NP_000135.2:p.Gly130Val
NP_852090.1:p.Gly130Val
LRG_339t1:c.389G>T
LRG_339:g.34380G>T
LRG_339p1:p.Gly130Val
NC_000009.11:g.71679858G>T
NM_000144.4:c.389G>T
Q16595:p.Gly130Val

Protein change:

G130V; GLY130VAL

Links:

UniProtKB: Q16595#VAR_002429; OMIM: 606829.0005; dbSNP: rs104894107

NCBI 1000 Genomes Browser:

rs104894107

Molecular consequence:

NM_000144.5:c.389G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_181425.3:c.389G>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
SCV001143968	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Nov 18, 2022)	unknown	clinical testing	PubMed (17) [See all records that cite these PMIDs] 17331979, 28812047, 26339677, 26704351, 10543403, 10732799, 11020385, 11030757, 11843702, 12019217, 18537827, 19494730, 19629184, 21298097, 9150176, 9989622, 26467025
SCV002064373	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 10, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002501403	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 26, 2021)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 9150176, 26301374, 11030757, 28812047, 20162437, 31980526, 11843702, 25741868
SCV005327016	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 21, 2024)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	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

Citations

PubMed

Mitochondrial frataxin interacts with ISD11 of the NFS1/ISCU complex and multiple mitochondrial chaperones.

Shan Y, Napoli E, Cortopassi G.

Hum Mol Genet. 2007 Apr 15;16(8):929-41. Epub 2007 Mar 1.

PubMed [citation]

PMID:: 17331979

Frataxin levels in peripheral tissue in Friedreich ataxia.

Lazaropoulos M, Dong Y, Clark E, Greeley NR, Seyer LA, Brigatti KW, Christie C, Perlman SL, Wilmot GR, Gomez CM, Mathews KD, Yoon G, Zesiewicz T, Hoyle C, Subramony SH, Brocht AF, Farmer JM, Wilson RB, Deutsch EC, Lynch DR.

Ann Clin Transl Neurol. 2015 Aug;2(8):831-42. doi: 10.1002/acn3.225. Epub 2015 Jul 1.

PubMed [citation]

PMID:: 26339677
PMCID:: PMC4554444

See all PubMed Citations (21)

Details of each submission

From Athena Diagnostics, SCV001143968.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (17)

Description

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 11030757, 18537827) In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.

#	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 Genetic Services Laboratory, University of Chicago, SCV002064373.1

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

Description

DNA sequence analysis of the FXN gene demonstrated a sequence change, c.389G>T, in exon 4 that results in an amino acid change, p.Gly130Val. The p.Gly130Val change affects a highly conserved amino acid residue located in a domain of the FXN protein that is known to be functional. The p.Gly130Val substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). PMID: 9150176 identified this sequence change in the compound heterozygous state with a GAA trinucleotide repeat expansion in three siblings with atypical Friedreich ataxia phenotype. PMID: 17331979 showed that this sequence change interfered with FXN protein expression in transfected HEK293T cells. This sequence change has been described in the genome Aggregation Database (gnomAD) with a very low population frequency of 0.0063% (dbSNP rs104894107).

#	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 AiLife Diagnostics, AiLife Diagnostics, SCV002501403.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (8)

#	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 GeneDx, SCV005327016.1

#	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); Published functional studies suggest a damaging effect with this variant resulting in a protein with a defect in protein processing (PMID: 28812047); 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: 9700204, 11020385, 17331979, 9989622, 26704351, 11030757, 20162437, 26301374, 9150176, 11843702, 26339677, 21298097, 19629184, 19494730, 18537827, 12019217, 10543403, 31980526, 28812047)

#	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: Oct 8, 2024

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