ClinVar Genomic variation as it relates to human health
NM_194279.4(ISCA2):c.229G>A (p.Gly77Ser)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_194279.4(ISCA2):c.229G>A (p.Gly77Ser)
Variation ID: 183353 Accession: VCV000183353.39
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q24.3 14: 74494329 (GRCh38) [ NCBI UCSC ] 14: 74961032 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Mar 16, 2015 Feb 14, 2024 Jun 14, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_194279.4:c.229G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_919255.2:p.Gly77Ser missense NM_001272007.2:c.174+177G>A intron variant NC_000014.9:g.74494329G>A NC_000014.8:g.74961032G>A NG_007117.1:g.4053C>T NG_033074.1:g.5610G>A Q86U28:p.Gly77Ser - Protein change
- G77S
- Other names
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- Canonical SPDI
- NC_000014.9:74494328:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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ISCA2 | - | - |
GRCh38 GRCh37 |
63 | 89 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (1) |
no assertion criteria provided
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Dec 1, 2014 | RCV000162184.10 | |
Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
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Jun 14, 2023 | RCV000170534.24 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 28, 2023 | RCV000255374.17 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 14, 2016 | RCV000310400.13 |
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
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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
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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. |
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Likely pathogenic
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Multiple Mitochondrial Dysfunctions Syndrome
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000388527.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
The c.229G>A (p.Gly77Ser) variant has been reported in two studies in a total of five multiple mitochondrial dysfunctions syndrome patients from three families, all of … (more)
The c.229G>A (p.Gly77Ser) variant has been reported in two studies in a total of five multiple mitochondrial dysfunctions syndrome patients from three families, all of whom were found to be homozygous for the variant (Alazami et al. 2015; Al-Hassnan et al. 2015). The p.Gly77Ser variant was shown to segregate with disease across two generations in all three families and to be the result of a founder effect. The variant was absent from 1,060 ethnically matched controls and is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. The Gly77 residue is highly conserved over 58 different species. Functional studies demonstrated that the p.Gly77Ser variant had only 20% of normal complex I activity and resulted in a significant depletion of mitochondrial DNA copy number in patient fibroblasts. Modelling studies showed that the p.Gly77Ser variant occurs in a loop that is directly involved in iron-sulphur cluster binding. Substitution of the glycine by serine is predicted to affect the stability of the flexibility of the loop and therefore the efficiency of binding to the iron-sulphur cluster (Alazami et al. 2015; Al-Hassnan et al. 2015). Based on the evidence, the p.Gly77Ser variant is classified as likely pathogenic for multiple mitochondrial dysfunctions syndrome. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Multiple mitochondrial dysfunctions syndrome 4
Affected status: yes
Allele origin:
germline
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Pathology and Clinical Laboratory Medicine, King Fahad Medical City
Accession: SCV000996287.1
First in ClinVar: Oct 20, 2019 Last updated: Oct 20, 2019 |
Number of individuals with the variant: 9
Ethnicity/Population group: Arab
Geographic origin: Middle East
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Pathogenic
(Oct 07, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000322178.7
First in ClinVar: Oct 09, 2016 Last updated: Apr 17, 2019 |
Comment:
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This … (more)
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29122497, 25558065, 25539947, 27959697, 29019354, 29297947, 30202406, 31130284, 32552793, 32342562) (less)
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Pathogenic
(Feb 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001578006.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ISCA2 function (PMID: 29297947). This sequence … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ISCA2 function (PMID: 29297947). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 77 of the ISCA2 protein (p.Gly77Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with multiple mitochondrial dysfunctions syndrome (PMID: 25558065, 29122497, 29297947). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 183353). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. (less)
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Pathogenic
(Nov 08, 2017)
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criteria provided, single submitter
Method: clinical testing
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Multiple mitochondrial dysfunctions syndrome 4
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV000680263.1
First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018 |
Sex: female
Tissue: blood
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Pathogenic
(May 08, 2023)
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criteria provided, single submitter
Method: research
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Multiple mitochondrial dysfunctions syndrome 4
Affected status: yes
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV003924350.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
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Pathogenic
(Jun 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Multiple mitochondrial dysfunctions syndrome 4
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002023177.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(May 01, 2016)
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no assertion criteria provided
Method: clinical testing
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Multiple mitochondrial dysfunctions syndrome 4
(Autosomal recessive inheritance)
Affected status: unknown, yes
Allele origin:
germline
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Baylor Genetics
Accession: SCV000328786.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Comment:
Our laboratory reported two molecular diagnoses in TUBB3 (NM_006086.3:c.982G>A) and ISCA2 (NM_194279.3:c.229G>A) in an individual with delayed motor milestones, developmental regression, hypotonia, hypertonia in extremities, … (more)
Our laboratory reported two molecular diagnoses in TUBB3 (NM_006086.3:c.982G>A) and ISCA2 (NM_194279.3:c.229G>A) in an individual with delayed motor milestones, developmental regression, hypotonia, hypertonia in extremities, increased reflexes with sustained ankle clonus bilaterally, macrocephaly, poor visual response withoptic nerve pallor, and brain imaging demonstrating demyelination and white matter disease. (less)
Observation 1: Observation 2: |
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Pathogenic
(Mar 01, 2015)
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no assertion criteria provided
Method: literature only
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MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 4
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000223099.3
First in ClinVar: May 24, 2015 Last updated: Jun 18, 2018 |
Comment on evidence:
In 6 patients from 5 consanguineous Arab families with multiple mitochondrial dysfunctions syndrome-4 (MMDS4; 616370), Al-Hassnan et al. (2015) identified a homozygous c.229G-A transition in … (more)
In 6 patients from 5 consanguineous Arab families with multiple mitochondrial dysfunctions syndrome-4 (MMDS4; 616370), Al-Hassnan et al. (2015) identified a homozygous c.229G-A transition in exon 3 of the ISCA2 gene (d.G74961032A), resulting in a gly77-to-ser (G77S) substitution at highly conserved residues in the Fe-S domain. The mutation, which was found by a combination of autozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The mutation was not found in the dbSNP or 1000 Genomes Project databases or in 1,060 chromosomes from ethnically matched controls. Haplotype analysis indicated a founder effect estimated to have occurred 4,802 years ago. Functional studies of the ISCA2 variant were not performed, but Al-Hassnan et al. (2015) noted that the ISCA2 gene is an essential component involved in the assembly of a mitochondrial iron-sulfur cluster (4Fe-4S) important for electron transfer and mitochondrial function. In 2 unrelated patients, each born of consanguineous Saudi parents, with MMDS4, Alaimo et al. (2018) identified a homozygous G77S mutation in the ISCA2 gene. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. In 10 children from 9 unrelated consanguineous Saudi families with MMDS4, Alfadhel et al. (2018) identified the homozygous G77S founder mutation in the ISCA2 gene. Specific functional studies of the variant were not performed, but laboratory studies suggested a defect in the 4Fe-4S cluster. (less)
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Likely pathogenic
(Dec 01, 2014)
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no assertion criteria provided
(research)
Method: research
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Neurodegeration
Global developmental delay Failure to thrive Spastic quadriplegia Truncal hypotonia Optic atrophy High CSF lactic acid Infantile death
Affected status: yes
Allele origin:
germline
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Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre
Accession: SCV000196470.1
First in ClinVar: Mar 16, 2015 Last updated: Mar 16, 2015 |
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Pathogenic
(Sep 15, 2019)
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no assertion criteria provided
Method: clinical testing
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Multiple mitochondrial dysfunctions syndrome 4
Affected status: yes
Allele origin:
germline
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Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001133009.1
First in ClinVar: Jan 06, 2020 Last updated: Jan 06, 2020 |
Number of individuals with the variant: 2
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Pathogenic
(Apr 01, 2023)
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no assertion criteria provided
Method: clinical testing
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Multiple mitochondrial dysfunctions syndrome 4
Affected status: yes
Allele origin:
germline
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Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)
Accession: SCV003927845.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
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not provided
(-)
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no classification provided
Method: literature only
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Multiple mitochondrial dysfunctions syndrome 4
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000747729.2
First in ClinVar: Feb 08, 2018 Last updated: Oct 01, 2022 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Loss-of-function mutations in ISCA2 disrupt 4Fe-4S cluster machinery and cause a fatal leukodystrophy with hyperglycinemia and mtDNA depletion. | Alaimo JT | Human mutation | 2018 | PMID: 29297947 |
Further delineation of the phenotypic spectrum of ISCA2 defect: A report of ten new cases. | Alfadhel M | European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society | 2018 | PMID: 29122497 |
Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. | Alazami AM | Cell reports | 2015 | PMID: 25558065 |
ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder. | Al-Hassnan ZN | Journal of medical genetics | 2015 | PMID: 25539947 |
Text-mined citations for rs730882246 ...
HelpRecord last updated May 27, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.