M-12417-CA-C

Position:

• chrM-12417-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 2)
• Consequence: ND5 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 Mitochondrial-myopathy-&-renal-failure
• Conservation: PhyloP100: 1.25

Genes affected

ND5 (HGNC:7461): (mitochondrially encoded NADH dehydrogenase 5) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Leigh disease; and MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• PP5: Variant M-12417-CA-C is Pathogenic according to our data. Variant chrM-12417-CA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 693440.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ND5	unassigned_transcript_4815	c.89delA	p.Asn30fs	frameshift_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap GenBank AF: 0.0 AC: 2

Alfa AF: 0.00111 Hom.: 0

Mitomap

Mitochondrial-myopathy-&-renal-failure

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial myopathy with reversible cytochrome C oxidase deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Oct 17, 2019

The NC_012920.1:m.12425delA (YP_003024036.1:p.Asn30ThrfsX7) variant in MTND5 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS6, PM8, PM9, PM10 -

Mitochondrial disease Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Nov 28, 2023

The m.12425del (p.N30TfsX7) variant in MT-ND5 has been reported in one individual to date, in a girl with mitochondrial myopathy and renal failure. In childhood, she was found to have impaired growth, mild metabolic acidosis, and elevated creatinine. After several years, her renal function declined, and she had daily vomiting and weight loss. Additionally, she had exercise intolerance and mild pigmentary retinopathy. She had received a donor kidney at the time of report and did well. She had persistently elevated blood lactate (5.1-5.9 mmol/L, normal 0.7-2.1). A renal biopsy showed glomerulocystic disease with significant atrophy and fibrosis. A muscle biopsy showed mild variation in fiber size with occasional atrophic, angulated fibers but no evidence of inflammatory changes and mild increase in lipid content. COX and SDH histochemistry revealed moderately increased enzyme activities in subsarcolemmal areas, subsarcolemmal mitochondrial accumulation, reduced complex I activity (with normal complex II+III and complex IV activities) and reduced fully assembled complex I. The variant was present at 85% heteroplasmy in muscle, 14% in blood, 19% in urine, and 22% in buccal sample (PMID: 20018511). As this is the only case reported to date, PS4 could not be applied. The variant was absent in blood, buccal, and urine samples from her healthy mother (PM6_supporting). Computational predictors are not applicable for this variant type precluding consideration for PP3 or BP4. This variant is present in population databases (Mitomap's 61,168 sequences: AF=0.007%; Helix's 196,554 sequences: AF=0.0005%; and gnomAD v3.1.2: AF=0.016% as this is heteroplasmic in 4 individuals). Given the frequency of this variant, it does not meet PM2 criterion. This variant results in a frameshift in codon 30, introducing a premature stop codon which predicts a truncation of the MT-ND5 protein from its full-length of 604 amino acids to 35 amino acids (PVS1_strong). 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 however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given biochemical evidence in the proband’s muscle is consistent with the predicted effect of this variant and because the variant is present at low heteroplasmy levels in the sequences in gnomAD v3.1.2. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 28, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PVS1_strong. -

MELAS syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Apr 06, 2022

_x000D_ Criteria applied: PVS1, PS3_SUP, PS4_SUP, PM2_SUP -

Leber optic atrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1603223730; hg19: chrM-12418;