rs387906421

Variant names:

• chrM-14674-T-C
• rs387906421
• unassigned_transcript_4817:c.69A>G

Your query was ambiguous. Multiple possible variants found:

• chrM-14674-T-C
• chrM-14674-T-G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS4 PS3_Supporting PP3

This summary comes from the ClinGen Evidence Repository: The m.14674T>C variant in MT-TE has been reported in at least 30 cases from 25 kindreds with primary mitochondrial disease. This variant is most commonly associated with reversible infantile respiratory chain deficiency (RIRCD), and has an estimated penetrance of 30% in reported families. The variant has been reported in the homoplasmic state in both affected and unaffected family members. There is one report of a heteroplasmic occurrence (90%) in a healthy mother. Age of onset in affected individuals generally ranged from birth to six weeks old, however there have been reports of weak fetal movements and one report with onset at four years old. Features include severe myopathy, feeding difficulty, and hypotonia that gradually improve over time, however mild myopathic features persist in many reported cases. Muscle biopsy findings in affected individuals include ragged red fibers, COX deficiency, and reduced respiratory chain enzyme activities in early biopsies that normalize on subsequent biopsies (PS4; PMIDs: 8155739, 19720722, 21194154, 21931168, 31333056, 33832841, 34732400, 34806237). There are no reported de novo occurrences of this variant to our knowledge. This variant is present in population databases which is to be expected given the known reduced penetrance of this variant (Mitomap: 56,910 sequences, AF=0.018%; Helix: 195,983 sequences, AF=0.006%; gnomAD v3.1.2: 56,429 sequences, AF=0.004% - homoplasmic in two individuals and heteroplasmic in three individuals). The computational predictor MitoTIP suggests this variant is pathogenic (29.4 percentile but confirmed pathogenicity) and HmtVAR predicts it to be pathogenic score of 0.8 (PP3). Several studies in skeletal muscle and primary cell cultures of affected individuals (PMID:19720722), cybrids (PMID:21194154), and transcriptome and proteomic analyses (PMID:33128823) support the functional impact of this variant (PS3_supporting). 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 January 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4, PP3, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120581/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNE unassigned_transcript_4817 splice_region, synonymous
• Scores: Mitotip Uncertain 9.6
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7 Reversible-COX-deficiency-myopathy,Reversible-COX-deficiency-myopathy
• Conservation: PhyloP100: -1.00
• Publications: 1 publications found

Genes affected

TRNE (HGNC:7479): (mitochondrially encoded tRNA glutamic acid)

MT-CYB (HGNC:7427): (mitochondrially encoded cytochrome b) Predicted to enable metal ion binding activity. Predicted to be involved in several processes, including electron transport coupled proton transport; response to cobalamin; and response to glucagon. Located in mitochondrion. Implicated in ovarian carcinoma and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND6 (HGNC:7462): (mitochondrially encoded NADH dehydrogenase 6) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Predicted to be located in mitochondrial inner membrane. Implicated in Leber hereditary optic neuropathy; Leigh disease; and spinal muscular atrophy with lower extremity predominante 2B. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND6 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• Leber hereditary optic neuropathy

  Inheritance: Mitochondrial Classification: STRONG, SUPPORTIVE Submitted by: G2P, Orphanet
• Leber plus disease

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• maternally-inherited Leigh syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• MELAS syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387459.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-TE	ENST00000387459.1	TSL:6	n.69A>G		splice_region non_coding_transcript_exon	Exon 1 of 1
	MT-CYB	ENST00000361789.2	TSL:6	c.-73T>C		upstream_gene	N/A	ENSP00000354554.2	P00156
	MT-ND6	ENST00000361681.2	TSL:6	c.-1A>G		upstream_gene	N/A	ENSP00000354665.2	P03923

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Gnomad homoplasmic AF: 0.000035 AC: 2 AN: 56429

Gnomad heteroplasmic AF: 0.000053 AC: 3 AN: 56429

Mitomap

Disease(s): Reversible-COX-deficiency-myopathy,Reversible-COX-deficiency-myopathy

Status: Cfrm-[LP],Reported

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Mitochondrial disease (3)
2	-	-	not provided (2)
1	-	-	MELAS syndrome (1)
1	-	-	Mitochondrial myopathy with reversible cytochrome C oxidase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	9.6
Hmtvar	Pathogenic	0.80
PhyloP100		-1.0

Other links and lift over

dbSNP: rs387906421; hg19: chrM-14675;