NM_024417.5(FDXR):c.1156C>T (p.Arg386Trp) AND Auditory neuropathy-optic atrophy syndrome

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Dec 13, 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:: RCV002470935.4

Allele description [Variation Report for NM_024417.5(FDXR):c.1156C>T (p.Arg386Trp)]

NM_024417.5(FDXR):c.1156C>T (p.Arg386Trp)

Gene:

FDXR:ferredoxin reductase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q25.1

Genomic location:

Preferred name:

NM_024417.5(FDXR):c.1156C>T (p.Arg386Trp)

HGVS:

NC_000017.11:g.74863914G>A
NM_001258012.4:c.1285C>T
NM_001258013.4:c.1249C>T
NM_001258014.4:c.1132C>T
NM_001258015.3:c.1036C>T
NM_001258016.3:c.1000C>T
NM_004110.6:c.1174C>T
NM_024417.5:c.1156C>TMANE SELECT
NP_001244941.2:p.Arg429Trp
NP_001244942.2:p.Arg417Trp
NP_001244943.2:p.Arg378Trp
NP_001244944.1:p.Arg346Trp
NP_001244945.2:p.Arg334Trp
NP_004101.3:p.Arg392Trp
NP_077728.3:p.Arg386Trp
NC_000017.10:g.72860036G>A
NM_001258012.3:c.1285C>T
NM_004110.3:c.1174C>T
NM_024417.4:c.1156C>T
NM_024417.5:c.1156C>T
NR_047576.3:n.1306C>T
NM_001258012.3:c.1174C>T

Protein change:

R334W; ARG392TRP

Links:

OMIM: 103270.0005; dbSNP: rs760345680

NCBI 1000 Genomes Browser:

rs760345680

Molecular consequence:

NM_001258012.4:c.1285C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258013.4:c.1249C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258014.4:c.1132C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258015.3:c.1036C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258016.3:c.1000C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004110.6:c.1174C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_024417.5:c.1156C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_047576.3:n.1306C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Auditory neuropathy-optic atrophy syndrome
Synonyms:: AUDITORY NEUROPATHY AND OPTIC ATROPHY; MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 9A
Identifiers:: MONDO: MONDO:0060582; MedGen: C4521678; OMIM: 617717

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002767780	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 19, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29040572, 25741868
SCV002796654	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 5, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003835487	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 13, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002767780

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 19, 2020)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002796654

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 5, 2021)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003835487

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 13, 2023)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Citations

PubMed

Biallelic mutations in the ferredoxin reductase gene cause novel mitochondriopathy with optic atrophy.

Peng Y, Shinde DN, Valencia CA, Mo JS, Rosenfeld J, Truitt Cho M, Chamberlin A, Li Z, Liu J, Gui B, Brockhage R, Basinger A, Alvarez-Leon B, Heydemann P, Magoulas PL, Lewis AM, Scaglia F, Gril S, Chong SC, Bower M, Monaghan KG, Willaert R, et al.

Hum Mol Genet. 2017 Dec 15;26(24):4937-4950. doi: 10.1093/hmg/ddx377. Erratum in: Hum Mol Genet. 2018 Jun 15;27(12):2224. doi: 10.1093/hmg/ddy072.

PubMed [citation]

PMID:: 29040572
PMCID:: PMC5886230

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002767780.1

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

Description

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with auditory neuropathy and optic atrophy (MIM#617717). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (45 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (6 heterozygotes, 0 homozygotes). (I) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0600 - Variant is located in the annotated NAD(P) binding domain (PMID: 29040572). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in multiple homozygous patients with mitochondriopathy with optic atrophy (ClinVar, PMID: 29040572). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. This variant causes reduced enzyme activity and overall mitochondrial dysfunction. Defects were rescued by overexpression of WT FDXR (PMID: 29040572). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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 Fulgent Genetics, Fulgent Genetics, SCV002796654.1

#	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

From Baylor Genetics, SCV003835487.2

#	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: Nov 24, 2024

ClinVar

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