Variant: NC_012920.1:m.1494C>T

CA254847

9632 (ClinVar)

Gene: N/A

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: fdc4a548-d997-49c2-a597-28c8119ada01

HGVS expressions

NC_012920.1:m.1494C>T
J01415.2:m.1494C>T

Likely Pathogenic

• Met criteria codes: PM5_Supporting PS3_Supporting PS4

• Not Met criteria codes: PS2 PP1 PP3 PM6 PM2

Expert Panel

Mitochondrial Diseases VCEP

Criteria Specification Information

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

Evidence submitted by expert panel

Mitochondrial Diseases VCEP

The m.1494C>T variant in the MT-RNR1 gene has been reported in >16 unrelated individuals with primary mitochondrial disease with non-syndromic hearing loss with and without aminoglycoside exposure. All were homoplasmic for the variant with the exception of one case who was heteroplasmic at 85.1% in blood (PS4; PMIDs: 34467602, 20100600, 17084680, 16380089, 17434445, 17698299, 17698030, 30693673, 14681830). Given the homoplasmic nature of this variant, familial segregation cannot be applied for PP1. There are no reports of de novo occurrences to our knowledge. This variant occurs in a highly conserved area and forms U1494-1555A base pair which is in the same position of the C1494-1555G pair created in a well-known pathogenic variant m.1555A>G (PM5_supporting; PMID: 14681830). Cybrid studies support the functional impact of this variant. Compared to control cybrids, there was a decrease in mitochondrial protein synthesis and high concentration of paromomycin in cybrids derived from three symptomatic and two asymptomatic individuals carrying the m.1494C>T variant (PS3_supporting; PMID: 15722487). This variant is present in population databases (Mitomap's 51,863 sequences: AF=0.007%; Helix's 196,554 sequences: AF=0.021%; and gnomAD v3.1.2: AF=0.0023% as this is homoplasmic in 13 individuals and heteroplasmic in one individual). Given the frequency of this variant, it does not meet PM2 criterion. There is limited computational scoring for rRNA variants precluding PP3 criterion. In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 11, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PS4, PM5_supporting.

Met criteria codes

• PM5_Supporting: This variant occurs in a highly conserved area and forms U1494-1555A base pair which is in the same position of the C1494-1555G pair created in a well-known pathogenic variant m.1555 A>G (PMID: 14681830).
• PS3_Supporting: Cybrid studies supported the functional impact of this variant including a decrease in mitochondrial protein synthesis and high concentration of paromomycin was observed in cybrids derived from three symptomatic and two asymptomatic individuals carrying the C1494T mutation, as compared to control cybrids (PMID15722487).
• PS4: This variant has been reported in >16 unrelated individuals with primary mitochondrial disease with non syndromic hearing loss with and without aminoglycoside exposure (PMIDs: 34467602, 20100600, 17084680, 16380089, 17434445, 17698299, 17698030, 30693673, 14681830).

Not Met criteria codes

• PS2: There are no reports of de novo occurrence of this variant.
• PP1: Given the homoplasmic nature of this variant familial segregation can not be applied.
• PP3: There is limited computational scoring for rRNA variants with a HmtVar score of 1 this is not enough to meet PP3 criteria.
• PM6: There are no reports of assumed de novo occurrence of this variant.
• PM2: This variant is present from Mitomap's 51,863 sequences (AF=0.007%); Helix's 196,554 sequences (AF=0.021%); and gnomAD v3.1.2 is 0.0023% seen homoplasmic in 13 individuals and heteroplasmic in 1 individual. Given the high frequency of this variant it does not meet PM2 criteria.

Approved on: 2022-07-11

Published on: 2022-10-12