VCV000370043.5 - ClinVar

NC_012920.1(MT-ND1):m.1661A>G

Germline

Top reviewed classifications are shown here.

Submission summary:

4 submissions

4 submitters

4 conditions

Reviewed by expert panel

Uncertain Significance

Oct 2023 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.1661A>G

Variation ID: 370043 Accession: VCV000370043.5

Type and length

single nucleotide variant, 1 bp

Location

MT: 1661 (GRCh38) [ NCBI UCSC ] MT: 1661 (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	Jan 4, 2017	May 19, 2024	Oct 23, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NC_012920.1:m.1661A>G

Protein change

Other names

1661A-G

Canonical SPDI

NC_012920.1:1660:A:G

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

ClinGen: CA16040644 OMIM: 590105.0003 dbSNP: rs1057516055 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-TV		-	-	GRCh38	32	33

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.
Axial hypotonia Developmental delay Epilepsy Hyperlactaemia	Uncertain significance (1)	no assertion criteria provided	Nov 21, 2016	RCV000408936.1
Charcot-Marie-Tooth disease, axonal, mitochondrial form, 1	Pathogenic (1)	no assertion criteria provided	May 15, 2024	RCV001281575.2
not specified	Uncertain significance (1)	criteria provided, single submitter	May 4, 2022	RCV002248638.1
Mitochondrial disease	Uncertain significance (1)	reviewed by expert panel	Oct 23, 2023	RCV003985323.1

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 (Oct 23, 2023)	reviewed by expert panel (McCormick et al. (Hum Mutat. 2020)) 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: SCV004801734.1 First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ce750f8c-53f8-4d28-9bb8-5a0bef5a665b Comment: The m.1661A>G variant in MT-TV has been reported in two unrelated families (PS4_supporting). Limited phenotypic details are provided in the first reported family (Patient 6 … (more) The m.1661A>G variant in MT-TV has been reported in two unrelated families (PS4_supporting). Limited phenotypic details are provided in the first reported family (Patient 6 in Bacalhau et al., 2017, PMID: 28027978) however a subsequent publication reported the proband in this family had seizures, hypotonia, developmental delay, elevated blood lactate, and combined deficiency of electron transport chain enzyme activities (PMID: 32715519). The heteroplasmy level and information on family members and/or testing in family members were not reported in this first kindred. The second family reported was a large kindred from the Venezuelan Andes with axonal Charcot-Marie-Tooth (CMT) disease (motor and sensory neuropathy). Muscle weakness, muscle atrophy, and ataxia were also seen in the affected individuals in this family (Fay et al., 2020, PMID: 32715519). Muscle biopsies performed in several individuals showed denervation and reinnervation, in addition to mitochondrial hyperplasia, mildly increased glycogen, and the presence of mitochondrial crystalline arrays. Combined respiratory chain enzyme deficiencies were also seen in affected individuals from this kindred. The variant was present at homoplasmy in blood and/or muscle in both affected and unaffected individuals from this kindred. There are no reported de novo occurrences on this variant to our knowledge. The computational predictor MitoTIP suggests this variant is benign (27.6 percentile; BP4).This variant is present in population databases (MITOMAP: 1/61,168 sequences, AF=0.002%, haplogroup (Hg) H1c; Helix: 2/195,983 (0.001%), also 19 heteroplasmic occurrences, homoplasmic occurrences in Hg I and V, heteroplasmic in multiple haplogroups; and gnomAD v3.1.2: 2/56,398 (0.004%), also three heteroplasmic occurrences (heteroplasmy levels: 10-20%; 20-30%; 90-100%), one in Hg T, one in H, one in B, one in K, one in L3). Given the frequency of this variant, it does not meet PM2 criterion. 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 October 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, BP4 (less)
Uncertain significance (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002518320.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Uncertain significance (Nov 21, 2016)	no assertion criteria provided Method: clinical testing	Epilepsy Axial hypotonia Developmental delay Hyperlactaemia Affected status: yes Allele origin: unknown	Center for Neuroscience and Cell Biology, University of Coimbra, Portugal Accession: SCV000484509.1 First in ClinVar: Jan 04, 2017 Last updated: Jan 04, 2017	Publications: PubMed (1) PubMed: 28027978 Number of individuals with the variant: 1 Sex: female
Pathogenic (May 15, 2024)	no assertion criteria provided Method: literature only	CHARCOT-MARIE-TOOTH DISEASE, AXONAL, MITOCHONDRIAL FORM, 1 (1 family) Affected status: not provided Allele origin: germline	OMIM Accession: SCV001468885.2 First in ClinVar: Jan 17, 2021 Last updated: May 19, 2024	Publications: PubMed (1) PubMed: 32715519 Comment on evidence: In an affected member of a large multigenerational Venezuelan family with mitochondrial form of axonal Charcot-Marie-Tooth disease-1 (CMTMA1; 500013), Fay et al. (2020) identified a … (more) In an affected member of a large multigenerational Venezuelan family with mitochondrial form of axonal Charcot-Marie-Tooth disease-1 (CMTMA1; 500013), Fay et al. (2020) identified a homoplasmic c.1661A-G transition in the MTTV gene, predicted to cause disruption of a base pair in the T-stem loop. The mutation, which was found by next-generation sequencing of mtDNA, was subsequently found in 4 additional family members, including 1 clinically asymptomatic individual, all of whom were homoplasmic for the mutation. These 3 affected individuals also had multiple large mtDNA deletions that were not found in the asymptomatic carrier. Northern blot analysis of muscle derived from the 4 patients showed decreased levels of mt-tRNA(Val) mRNA compared to controls. Patient muscle tissue also showed reduced activities of multiple enzymes in the mitochondrial respiratory chain complex, including I+III and IV. The reduction in enzyme activity was greater in those who were more severely affected. The findings suggested mitochondrial dysfunction as a cause of the disorder. (less)

Comment:

The m.1661A>G variant in MT-TV has been reported in two unrelated families (PS4_supporting). Limited phenotypic details are provided in the first reported family (Patient 6 in Bacalhau et al., 2017, PMID: 28027978) however a subsequent publication reported the proband in this family had seizures, hypotonia, developmental delay, elevated blood lactate, and combined deficiency of electron transport chain enzyme activities (PMID: 32715519). The heteroplasmy level and information on family members and/or testing in family members were not reported in this first kindred. The second family reported was a large kindred from the Venezuelan Andes with axonal Charcot-Marie-Tooth (CMT) disease (motor and sensory neuropathy). Muscle weakness, muscle atrophy, and ataxia were also seen in the affected individuals in this family (Fay et al., 2020, PMID: 32715519). Muscle biopsies performed in several individuals showed denervation and reinnervation, in addition to mitochondrial hyperplasia, mildly increased glycogen, and the presence of mitochondrial crystalline arrays. Combined respiratory chain enzyme deficiencies were also seen in affected individuals from this kindred. The variant was present at homoplasmy in blood and/or muscle in both affected and unaffected individuals from this kindred. There are no reported de novo occurrences on this variant to our knowledge. The computational predictor MitoTIP suggests this variant is benign (27.6 percentile; BP4).This variant is present in population databases (MITOMAP: 1/61,168 sequences, AF=0.002%, haplogroup (Hg) H1c; Helix: 2/195,983 (0.001%), also 19 heteroplasmic occurrences, homoplasmic occurrences in Hg I and V, heteroplasmic in multiple haplogroups; and gnomAD v3.1.2: 2/56,398 (0.004%), also three heteroplasmic occurrences (heteroplasmy levels: 10-20%; 20-30%; 90-100%), one in Hg T, one in H, one in B, one in K, one in L3). Given the frequency of this variant, it does not meet PM2 criterion. 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 October 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, BP4

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
A Mitochondrial tRNA Mutation Causes Axonal CMT in a Large Venezuelan Family.	Fay A	Annals of neurology	2020	PMID: 32715519
In silico analysis for predicting pathogenicity of five unclassified mitochondrial DNA mutations associated with mitochondrial cytopathies' phenotypes.	Bacalhau M	European journal of medical genetics	2017	PMID: 28027978
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ce750f8c-53f8-4d28-9bb8-5a0bef5a665b	-	-	-	-

Text-mined citations for rs1057516055 ...

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 May 27, 2024

ClinVar Genomic variation as it relates to human health

NC_012920.1(MT-ND1):m.1661A>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1057516055 ...