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]
  • 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.10158T>C") does not appear to be in HGVS format
  • See Evidence submitted by expert panel for details.

Variant: m.10158T>C

CA120639

9714 (ClinVar)

Gene: MT-ND3
Condition: mitochondrial disease
Inheritance Mode: Mitochondrial inheritance
Link to MONDO
UUID: a6286886-7f30-4c11-8ebb-5a936eb6f1c9
Approved on: 2021-10-26
Published on: 2021-10-26

HGVS expressions

NC_012920.1:m.10158T>C
J01415.2:m.10158T>C
ENST00000361227.2:n.100T>C

Pathogenic

Met criteria codes 6
PM2_Supporting PS3_Supporting PM6_Strong PS4 PP1 PP3
Not Met criteria codes 12
PM4 PM5 BA1 BS4 BS3 BS1 PVS1 BS2 BP5 BP7 BP2 PS1

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Mitochondrial Diseases VCEP
The m.10158T>C (p.S34P) variant in MT-ND3 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant has been reported in >16 individuals with primary mitochondrial disease with onset ranging from the first year of life to adulthood and who had features variably consistent with Leigh syndrome, MELAS and MELAS-like, and/or lactic acidosis (PS4; PMID: 14705112; PMID: 14684687; PMID: 27348141; PMID: 28050007; PMID: 27742419; PMID: 28916229; PMID: 14764913; PMID: 22115768; PMID: 15576045; PMID: 30128709; PMID: 29237403; PMID: 31178082; https://doi.org/10.1111/ncn3.17). This variant has been identified as a de novo occurrence in at least seven probands with primary mitochondrial disease (PM6_strong; PMID: 28916229; PMID: 14764913; PMID: 14705112; PMID: 14684687; PMID: 31178082). This variant segregated with disease in multiple members in at least two families (PP1; PMID: 27742419; PMID: 14705112) and one healthy mother was found to have the variant at low heteroplasmy level (PMID: 14705112). This variant is absent from Mitomap's GenBank sequences and gnomAD v3.1.2 (PM2_Supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.95 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies showed tight correlation between variant heteroplasmy level and complex I activity (PS3_supporting; PMID: 14705112). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PS4, PM2_supporting, PM6_strong, PP1, PP3).
Met criteria codes
PM2_Supporting
This variant is absent from Mitomap's GenBank sequences and gnomAD v3.1.2 (PM2_Supporting; query updated 3/22/2021).
PS3_Supporting
Cybrid studies meeting criteria (showing tight correlation between % mutant and CI activity)
Cybrid studies meeting criteria, however not reproduced so did not increase weight further PubMed:14705112
PM6_Strong
This variant has been identified as a de novo occurrence with unconfirmed parental relationships in at least 7 probands with primary mitochondrial disease (PM6_strong; PMID: 28916229; PMID: 14764913; PMID: 14705112; PMID: 14684687; PMID: 31178082). Per SVI de novo guidance Table 1 “phenotypic consistency” category of “phenotype consistent with gene but not highly specific” total is 3.5 points = strong
PS4
This variant has been reported in >16 individuals with primary mitochondrial disease with onset ranging from the first year of life to adulthood and who had features variably consistent with Leigh syndrome, MELAS and MELAS-like, and/or lactic acidosis (PS4; PMID: 14705112; PMID: 14684687; PMID: 27348141; PMID: 28050007; PMID: 27742419; PMID: 28916229; PMID: 14764913; PMID: 22115768; PMID: 15576045; PMID: 30128709; PMID: 29237403; PMID: 31178082; https://doi.org/10.1111/ncn3.17).
PP1
This variant segregated with disease in multiple (three) members in at least two families, meeting specified criteria for PP1 [PP1; PMID: 27742419 (Grosso et al., 2017 - Healthy mother with lower heteroplasmy levels - 70% in urinary epithelium, 50% in buccal epithelium and 10% in lymphocytes) and PMID: 14705112 (McFarland et al., 2004 - Patient 3 (mother healthy and lower heteroplasmy (7% in FCL), sibling healthy and variant is undetectable)].
PP3
The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.95 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3).
Not Met criteria codes
PM4
Not an insertion/deletion
PM5
No other amino acid change reported at this site to be pathogenic (MITOMAP reports several other sequence variants in nt positions 10155-10161, however none are confirmed to be pathogenic and none lead to same amino acid change - query updated on 6/23/2020)
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
This is not a large mtDNA deletion
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No other nucleotide variant leading to same amino acid change reported at this site to be pathogenic (MITOMAP reports several other sequence variants in nt positions 10155-10161, however none are confirmed to be pathogenic and none lead to same amino acid change - query updated on 6/23/2020)
Curation History
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