Submissions for variant NC_012920.1(MT-ND1):m.3502T>C

dbSNP: rs1603218987

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV004792554	SCV005407791	uncertain significance	Mitochondrial disease	2024-09-24	reviewed by expert panel	curation	The m.3502T>C (p.S66P) variant in MT-ND1 has been reported in one individual with primary mitochondrial disease to date however clinical details are not provided (PMID: 32652755). There is also a ClinVar submission from the Undiagnosed Diseases Network however it is not clear if this is a second unrelated case or the same case as reported in the medical literature. There are no additional individuals or families reported with de novo occurrences of this variant or with this variant segregating with clinical manifestations to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of neutral with a score of 0.36 (Min=0, Max=1; APOGEE2 score is 0.824). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance 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 September 24, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000853665	SCV000996694	likely pathogenic	Mitochondrial myopathy with reversible cytochrome C oxidase deficiency	2019-10-17	criteria provided, single submitter	clinical testing	The NC_012920.1:m.3502T>C (YP_003024026.1:p.Ser66Pro) variant in MTND1 gene is interpretated to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished).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: PM2, PM8, PM9, PP4, PP6
Undiagnosed Diseases Network, NIH	RCV002252257	SCV002523180	likely pathogenic	MELAS syndrome	2022-04-11	criteria provided, single submitter	clinical testing	Heteroplasmy at 7.2% in blood and 96.5% in muscle. Structural biology analysis found this variant to be disruptive to protein function. Muscle biopsy found changes suggestive of mitochondrial myopathy as indicated by ragged red (modified trichrome reaction) and ragged blue (SDH) fibers.