Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
Link to SEPIO compliant JSON-LD document
  • There was no gene found in the curated document received from the VCI/VCEP
  • Gene listed was thus derived from ClinVar and/or CAR
  • The variant label for this record ("m.4171C>A") does not appear to be in HGVS format

Variant: m.4171C>A

CA340948

9732 (ClinVar)

Gene: MT-ND1
Condition: mitochondrial disease
Inheritance Mode: Mitochondrial inheritance
Link to MONDO
UUID: a82351f9-067f-44c7-801d-bb572306b8ff

HGVS expressions

NC_012920.1:m.4171C>A
J01415.2:m.4171C>A
ENST00000361390.2:n.865C>A

Uncertain Significance

Met criteria codes 3
PM2_Supporting PP3 PS4_Moderate
Not Met criteria codes 4
PS2 PS3 PP1 PM6

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_mtDNA

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Mitochondrial Diseases VCEP
The m.4171C>A (p.L289M) variant in MT-ND1 has been reported in 13 individuals with primary mitochondrial disease with features falling under the LHON and/or Leigh syndrome spectrums with variable brain lesions (PS4_moderate, PMIDs: 12112111, 19555656, 20491810, 22879922, 24884847, 32652755, 34670133, 35104579, 32045392; Cui et al., 2006 with no PMID; of note, the two families in PMID: 12112111 might be in the same haplogroup although there is no known kinship). Additionally, this expert panel knew of one local family with an affected individual with this variant that the expert panel agreed to include. There are no reports of de novo occurrences to our knowledge. Although typically homoplasmic in kindreds, the variant has been reported to segregate with features of primary mitochondrial disease in two family members from one family (PMID: 12112111) however this did not meet criteria to be considered for PP1. This variant is absent in population databases after removing sequences from individuals with mitochondrial disease (two occurrences in GenBank sequences are from individuals with mitochondrial disease; absent in gnomAD v3.1.2 and Helix dataset; PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.60 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). An E. coli model (homoplasmic for this variant) showed only a 13% decrease in enzyme activity, which did not reach statistical significance and therefore did not meet criteria to be considered for PS3 (PMID: 19616643). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. In the future, once three or more unrelated cases are reported, criteria for a likely pathogenic classification would be met. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on April 11, 2022 (PMID: 32906214): Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM2_supporting, PP3.
Met criteria codes
PM2_Supporting
This variant is absent in population databases after removing sequences from individuals with mitochondrial disease (two occurrences in GenBank sequences are from individuals with mitochondrial disease; absent in gnomAD v3.1.2 and Helix dataset; PM2_supporting). AF = 0% in gnomAD & Helix databases; 2/54594 Genbank sequences are reported in Mitomap but they are LHON patients from Yang 2009 PMID19555656 and La Morgia 2014 PMID24884847.
PP3
The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.60 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3).
PS4_Moderate
The m.4171C>A (p.L289M) variant in MT-ND1 has been reported in 13 individuals with primary mitochondrial disease with features falling under the LHON and/or Leigh syndrome spectrums with variable brain lesions (PS4_moderate, PMIDs: 12112111, 19555656, 20491810, 22879922, 24884847, 32652755, 34670133, 35104579, 32045392; Cui et al., 2006 with no PMID; of note, the two families in PMID: 12112111 might be in the same haplogroup although there is no known kinship). Additionally, this expert panel knew of one local family with an affected individual with this variant that the expert panel agreed to include.
Not Met criteria codes
PS2
There are no reports of de novo occurrences to our knowledge.
PS3
An E. coli model (homoplasmic for this variant) showed only a 13% decrease in enzyme activity, which did not reach statistical significance and therefore did not meet criteria to be considered for PS3 (PMID: 19616643). E coli model (PMID: 19616643) showed mild decrease in function. Although not statistically significant, this could be appropriate for the many cases with this mutation that have shown to have visual recovery.
PP1
Although typically homoplasmic in kindreds, the variant has been reported to segregate with features of primary mitochondrial disease in two family members from one family (PMID: 12112111) however this did not meet criteria to be considered for PP1. This mutation is usually homoplasmic. So far only 1 heteroplasmic segregation has been clearly noted in the literature, and it's not too impressive (100% in proband, 88% in unaffected mom.)
PM6
There are no reports of de novo occurrences to our knowledge.
Approved on: 2022-06-30
Published on: 2022-06-30
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