NM_001098.3(ACO2):c.220C>G (p.Leu74Val) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (7 submissions)
Last evaluated:: Jan 29, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000676884.48

Allele description [Variation Report for NM_001098.3(ACO2):c.220C>G (p.Leu74Val)]

NM_001098.3(ACO2):c.220C>G (p.Leu74Val)

Gene:

ACO2:aconitase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

22q13.2

Genomic location:

Preferred name:

NM_001098.3(ACO2):c.220C>G (p.Leu74Val)

Other names:

ACO2, LEU74VAL (rs141772938)

HGVS:

NC_000022.11:g.41507837C>G
NG_032143.1:g.43713C>G
NM_001098.3:c.220C>GMANE SELECT
NP_001089.1:p.Leu74Val
NC_000022.10:g.41903841C>G
NM_001098.2:c.220C>G
Q99798:p.Leu74Val

Protein change:

L74V; LEU74VAL

Links:

UniProtKB: Q99798#VAR_073435; OMIM: 100850.0002; dbSNP: rs141772938

NCBI 1000 Genomes Browser:

rs141772938

Molecular consequence:

NM_001098.3:c.220C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000251043	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Apr 3, 2023)	germline	clinical testing	Citation Link,
SCV000701819	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Oct 12, 2016)	germline	clinical testing	Citation Link,
SCV000802698	Mayo Clinic Laboratories, Mayo Clinic	no assertion criteria provided	Uncertain significance (Feb 26, 2016)	unknown	clinical testing
SCV000892333	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely benign (Nov 1, 2023)	germline	clinical testing	Citation Link,
SCV001025827	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Benign (Jan 29, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001553452	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Uncertain significance	unknown	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	11	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From GeneDx, SCV000251043.12

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Functional data demonstrated that the mutant protein failed to rescue mitochondrial aconitase deficient yeast strain (Metodiev et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28463998, 29577077, 34056600, 31106992, 30689204, 31765440, 32519519, 34426522, 34354088, 34234304, 25351951, 32449285, 30831606, 30118607)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Eurofins Ntd Llc (ga), SCV000701819.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV000802698.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV000892333.23

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	11	not provided	not provided	clinical testing	not provided

Description

ACO2: BP5, BS2

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		11	not provided	not provided	not provided

From Invitae, SCV001025827.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001480164.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001553452.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The ACO2 p.Leu74Val variant was identified in the literature in two adult male siblings with optic atrophy beginning in childhood; the p.L74V variant was found as a compound heterozygous mutation with a ACO2 p.G661R variant. Decreased ACO2 protein levels were observed in fibroblasts from these two patients (Metodiev_2014_PMID:25351951). The variant was identified in dbSNP (ID: rs141772938) and ClinVar (classified as uncertain significance by Fulgent Genetics, GeneDx, EGL Genetics and Mayo Clinic, and as likely pathogenic by CeGaT Praxis fuer Humangenetik Tuebingen). The variant was identified in control databases in 1055 of 282256 chromosomes (4 homozygous) at a frequency of 0.003738 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 839 of 128790 chromosomes (freq: 0.006514), Other in 30 of 7208 chromosomes (freq: 0.004162), European (Finnish) in 80 of 25082 chromosomes (freq: 0.00319), South Asian in 52 of 30602 chromosomes (freq: 0.001699), African in 23 of 24894 chromosomes (freq: 0.000924) and Latino in 31 of 35394 chromosomes (freq: 0.000876), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.Leu74 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001480164	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None (ACMG Guidelines, 2015)	Likely pathogenic (Feb 1, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001480164

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 1, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Last Updated: Jun 9, 2024

Relating variation to medicine