M-13513-G-C

Variant names:

• chrM-13513-G-C
• rs267606897
• ENST00000361567.2:c.1177G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The ENST00000361567.2(MT-ND5):​c.1177G>C​(p.Asp393His) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 7/11 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D393G) has been classified as Likely pathogenic.

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 1)
• Consequence: MT-ND5 ENST00000361567.2 missense
• Scores: Apogee2 Pathogenic 0.83
• Clinical Significance: Not reported in ClinVar No linked disesase in Mitomap
• Conservation: PhyloP100: 9.29
• Publications: 42 publications found

Genes affected

MT-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]

MT-ND5 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: Orphanet, G2P
• maternally-inherited Leigh syndrome

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

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

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrM-13514-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 155889.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: Apogee2 supports a deletorius effect, 0.8342808 >= 0.5 .

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND5	unassigned_transcript_4815	c.1177G>C	p.Asp393His	missense_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND5	ENST00000361567.2	c.1177G>C	p.Asp393His	missense_variant	Exon 1 of 1	6		ENSP00000354813.2

Frequencies

Mitomap GenBank AF: 0.0 AC: 1

Mitomap

No disease associated.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.83
Hmtvar	Pathogenic	0.89
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.018	T
DEOGEN2	Benign	0.24	T
LIST_S2	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		9.3
PROVEAN	Pathogenic	-6.3	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.5
Varity_R		0.91
Mutation Taster		=14/86	disease causing

Other links and lift over

dbSNP: rs267606897; hg19: chrM-13514;