m.4171C>A AND Leber optic atrophy

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: May 4, 2022
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:: RCV000010384.9

Allele description [Variation Report for m.4171C>A]

m.4171C>A

Gene:

MT-ND1:mitochondrially encoded NADH dehydrogenase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Genomic location:

Preferred name:

m.4171C>A

HGVS:

NC_012920.1:m.4171C>A
YP_003024026.1:p.Leu289Met
AC_000021.2:m.4171C>A
NC_012920.1:g.4171C>A

Links:

OMIM: 516000.0010; dbSNP: rs28616230

NCBI 1000 Genomes Browser:

rs28616230

Condition(s)

Name:: Leber optic atrophy (LHON)
Synonyms:: Optic Atrophy, Hereditary, Leber; Leber hereditary optic neuropathy; Leber's disease; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010788; MedGen: C0917796; Orphanet: 104; OMIM: 535000; Human Phenotype Ontology: HP:0001112

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000030610	OMIM	no assertion criteria provided	Pathogenic (May 1, 2002)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000086638	GeneReviews	no classification provided	not provided	maternal	literature only	PubMed (2) [See all records that cite these PMIDs] 30143805, 20301353
SCV000996776	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	criteria provided, single submitter (Modified ACMG Guidelines (Unpublished))	Likely pathogenic (Oct 17, 2019)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12112111, 15972314, 22879922, 24884847, 19555656 Citation Link,
SCV002517669	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2019)	Pathogenic (May 4, 2022)	germline	clinical testing	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	maternal	unknown	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clinical utility gene card for: inherited optic neuropathies including next-generation sequencing-based approaches.

Jurkute N, Majander A, Bowman R, Votruba M, Abbs S, Acheson J, Lenaers G, Amati-Bonneau P, Moosajee M, Arno G, Yu-Wai-Man P.

Eur J Hum Genet. 2019 Mar;27(3):494-502. doi: 10.1038/s41431-018-0235-y. Epub 2018 Aug 24. No abstract available.

PubMed [citation]

PMID:: 30143805
PMCID:: PMC6460557

Leber Hereditary Optic Neuropathy.

Yu-Wai-Man P, Chinnery PF.

2000 Oct 26 [updated 2021 Mar 11]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 20301353

See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000030610.2

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

Description

In 2 Korean families with LHON (535000), Kim et al. (2002) identified a 4171C-A mutation in the MTND1 gene, resulting in a leu289-to-met substitution in a highly conserved region of an extramembrane loop. All 4 patients recovered spontaneously after suffering months to years following initial visual loss. The authors noted that the mutation does not alter the side-chain hydrophobicity, which they believed resulted in a good clinical prognosis because of the slight changes in the amino acid, and thus the protein, characteristics.

#	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 GeneReviews, SCV000086638.3

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

Description

This mitochondrial DNA variant affects function. It hase been identified in at least two independent LHON pedigrees and segregates with affected disease status.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV000996776.1

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

Description

The NC_012920.1:m.4171C>A (YP_003024026.1:p.Leu289Met) variant in MTND1 gene is interpretated to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS1, PM9, PP4

#	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 Mendelics, SCV002517669.1

#	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

Last Updated: Dec 9, 2023

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