Submissions for variant NM_194279.4(ISCA2):c.229G>A (p.Gly77Ser)

dbSNP: rs730882246

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255374	SCV000322178	pathogenic	not provided	2020-10-07	criteria provided, single submitter	clinical testing	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)
Illumina Laboratory Services, Illumina	RCV000310400	SCV000388527	likely pathogenic	Fatal multiple mitochondrial dysfunctions syndrome	2016-06-14	criteria provided, single submitter	clinical testing	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.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000170534	SCV000680263	pathogenic	Multiple mitochondrial dysfunctions syndrome 4	2017-11-08	criteria provided, single submitter	clinical testing
Pathology and Clinical Laboratory Medicine, King Fahad Medical City	RCV000170534	SCV000996287	pathogenic	Multiple mitochondrial dysfunctions syndrome 4		criteria provided, single submitter	clinical testing
Invitae	RCV000255374	SCV001578006	pathogenic	not provided	2023-02-28	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV000170534	SCV002023177	pathogenic	Multiple mitochondrial dysfunctions syndrome 4	2023-06-14	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000170534	SCV003924350	pathogenic	Multiple mitochondrial dysfunctions syndrome 4	2023-05-08	criteria provided, single submitter	research
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre	RCV000162184	SCV000196470	likely pathogenic	Global developmental delay; Failure to thrive; Spastic tetraplegia; Optic atrophy; Axial hypotonia; Death in infancy; High CSF lactic acid; Neurodegeration	2014-12-01	no assertion criteria provided	research
OMIM	RCV000170534	SCV000223099	pathogenic	Multiple mitochondrial dysfunctions syndrome 4	2015-03-01	no assertion criteria provided	literature only
Baylor Genetics	RCV000170534	SCV000328786	pathogenic	Multiple mitochondrial dysfunctions syndrome 4	2016-05-01	no assertion criteria provided	clinical testing	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.
GeneReviews	RCV000170534	SCV000747729	not provided	Multiple mitochondrial dysfunctions syndrome 4		no assertion provided	literature only
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000170534	SCV001133009	pathogenic	Multiple mitochondrial dysfunctions syndrome 4	2019-09-15	no assertion criteria provided	clinical testing
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV000170534	SCV003927845	pathogenic	Multiple mitochondrial dysfunctions syndrome 4	2023-04-01	no assertion criteria provided	clinical testing