rs199476124

Variant names:

• chrM-3949-T-C
• rs199476124
• unassigned_transcript_4789:c.643T>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 1)
• Consequence: ND1 missense
• Scores: Apogee2 Pathogenic 0.64
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 O:1 MELAS
• Conservation: PhyloP100: 7.58

Genes affected

ND1 (HGNC:7455): (mitochondrially encoded NADH dehydrogenase 1) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Located in mitochondrial membrane. Part of mitochondrial respiratory chain complex I. Implicated in several diseases, including MELAS syndrome; neurodegenerative disease (multiple); optic nerve disease (multiple); toxic shock syndrome; and type 2 diabetes mellitus. Biomarker of Alzheimer's disease; Parkinson's disease; and multiple sclerosis. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• PP5: Variant M-3949-T-C is Pathogenic according to our data. Variant chrM-3949-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 9735.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND1	unassigned_transcript_4789	c.643T>C	p.Tyr215His	missense_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	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: 1

Mitomap

MELAS

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

MELAS syndrome Pathogenic:1 Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Uncertain:1

Aug 22, 2023

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

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The m.3949T>C (p.Y215H) variant in MT-ND1 has been reported in one individual to date with primary mitochondrial disease. This individual had features consistent with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) and harbored the variant at 93% heteroplasmy in muscle, 45% in blood, and 88% in fibroblasts (PMID:15466014). This variant occurred de novo in one individual (absent in blood from mother and two brothers; PM6_supporting, PMID: 15466014). Electron transport chain (ETC) enzyme activity in fibroblasts and muscles was consistent with severe isolated defect of complex I, and levels of assembled complex I was approximately 12% of control; however, nuclear etiologies were not excluded (PMID: 15466014). Studies in E. coli (PMID: 16849371) and cybrids (PMID: 15466014) support the functional impact of this variant and independent studies showed independent deleterious effects of the variant (PS3_supporting). The m.3949GT>C variant is present in Mitomap’s GenBank dataset at less than 1/50,000 or 0.002% (1/61,168 sequences, 0.00163%, haplogroup K1a). This variant is absent in gnomAD v3.1.2 and in Helix dataset therefore this variant is absent in healthy individuals (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.54 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). 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 August 22, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PS3_supporting, PP3, PM2_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.64
Hmtvar	Pathogenic	0.84
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.031	T
DEOGEN2	Benign	0.23	T
LIST_S2	Benign	0.81	T
MutationAssessor	Pathogenic	3.6	H
PROVEAN	Pathogenic	-4.7	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.5
Varity_R		0.93

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199476124; hg19: chrM-3950;