VCV000692361.4 - ClinVar

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

Germline

Top reviewed classifications are shown here.

Submission summary:

3 submissions

3 submitters

3 conditions

Reviewed by expert panel

Uncertain Significance

Sep 2024 by ClinGen Mitoch… FDA Recognized Database

for Mitochondrial disease

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 692361 Accession: VCV000692361.4

Type and length

single nucleotide variant, 1 bp

Location

MT: 3502 (GRCh38) [ NCBI UCSC ] MT: 3502 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Nov 2, 2019	Nov 24, 2024	Sep 24, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NC_012920.1:m.3502T>C

Protein change

Other names

p.Ser66Pro

Canonical SPDI

NC_012920.1:3501:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

dbSNP: rs1603218987 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MT-ND1		-	-	GRCh38	180	184

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Mitochondrial myopathy with reversible cytochrome C oxidase deficiency	Likely pathogenic (1)	criteria provided, single submitter	Oct 17, 2019	RCV000853665.1
Juvenile myopathy, encephalopathy, lactic acidosis AND stroke	Likely pathogenic (1)	criteria provided, single submitter	Apr 11, 2022	RCV002252257.2
Mitochondrial disease	Uncertain significance (1)	reviewed by expert panel	Sep 24, 2024	RCV004792554.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain Significance (Sep 24, 2024)	reviewed by expert panel (clingen mito disease acmg specifications v1-1) Method: curation	Mitochondrial disease (Mitochondrial inheritance) Affected status: unknown Allele origin: germline	ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen FDA Recognized Database Accession: SCV005407791.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/efa31fe4-9312-4e6d-8974-e5982d5b7272 Comment: 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: … (more) 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. (less)
Likely pathogenic (Oct 17, 2019)	criteria provided, single submitter (Modified ACMG Guidelines (Unpublished)) Method: clinical testing	Mitochondrial myopathy with reversible cytochrome C oxidase deficiency Affected status: unknown Allele origin: germline	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine Accession: SCV000996694.1 First in ClinVar: Nov 02, 2019 Last updated: Nov 02, 2019	Comment: 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 … (more) 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 (less)
Likely pathogenic (Apr 11, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Juvenile myopathy, encephalopathy, lactic acidosis AND stroke (Mitochondrial inheritance) Affected status: yes Allele origin: de novo	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV002523180.1 First in ClinVar: Jun 10, 2022 Last updated: Jun 10, 2022	Comment: 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 … (more) 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. (less) Number of individuals with the variant: 1 Clinical Features: Seizure (present) , Mental deterioration (present) , Ragged-red muscle fibers (present) , Inborn mitochondrial myopathy (present) Age: 10-19 years Sex: male

Comment:

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.

Comment:

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

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/efa31fe4-9312-4e6d-8974-e5982d5b7272	-	-	-	-

Text-mined citations for rs1603218987 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1603218987 ...