Variant: m.10158T>C

CA120639

9714 (ClinVar)

Gene: MT-ND3

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: a6286886-7f30-4c11-8ebb-5a936eb6f1c9

HGVS expressions

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

Pathogenic

• Met criteria codes: PM2_Supporting PM6_Strong PS3_Supporting PP1 PP3 PS4

• Not Met criteria codes: PVS1 BA1 BP2 BP5 BP7 BS2 BS4 BS3 BS1 PM4 PM5 PS1

Expert Panel

Mitochondrial Diseases VCEP

Criteria Specification Information

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).
• 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
• PS3_Supporting: Cybrid studies meeting criteria (showing tight correlation between % mutant and CI activity)
• 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).
• 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).

Not Met criteria codes

• PVS1: This is not a large mtDNA deletion
• BA1: 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
• 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
• BS2: 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
• 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)
• 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)

Approved on: 2021-10-26

Published on: 2021-10-26