rs730882246

Positions:

• chr14-74494329-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_194279.4(ISCA2):​c.229G>A​(p.Gly77Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ISCA2 NM_194279.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 9.64

Genes affected

ISCA2 (HGNC:19857): (iron-sulfur cluster assembly 2) The protein encoded by this gene is an A-type iron-sulfur cluster (ISC) protein found in mitochondria. The encoded protein appears to be involved in the maturation of mitochondrial iron-sulfur proteins. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866
• PP5: Variant 14-74494329-G-A is Pathogenic according to our data. Variant chr14-74494329-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-74494329-G-A is described in Lovd as [Pathogenic]. Variant chr14-74494329-G-A is described in Lovd as [Likely_pathogenic]. Variant chr14-74494329-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ISCA2	NM_194279.4	c.229G>A	p.Gly77Ser	missense_variant	3/4	ENST00000556816.6
ISCA2	NM_001272007.2	c.174+177G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ISCA2	ENST00000556816.6	c.229G>A	p.Gly77Ser	missense_variant	3/4	1	NM_194279.4	P1
ISCA2	ENST00000298818.12	c.229G>A	p.Gly77Ser	missense_variant	3/4	5
ISCA2	ENST00000554924.1	c.174+177G>A		intron_variant		2
ISCA2	ENST00000555139.1	n.232G>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple mitochondrial dysfunctions syndrome 4 Pathogenic:8 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Pathology and Clinical Laboratory Medicine, King Fahad Medical City	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 15, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 14, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2015	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	May 01, 2016	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. -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	May 08, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	Apr 01, 2023	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 28, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 07, 2020	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) -

Fatal multiple mitochondrial dysfunctions syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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. -

Optic atrophy;C0426970:Spastic tetraplegia;C0557874:Global developmental delay;C1853743:Axial hypotonia;C1858430:Death in infancy;C2315100:Failure to thrive;CN228271:High CSF lactic acid;CN228311:Neurodegeration Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Dec 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.0	D;D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.83
MutPred		0.62		Gain of catalytic residue at G78 (P = 6e-04);Gain of catalytic residue at G78 (P = 6e-04);
MVP		0.69
MPC		1.5
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.93
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs730882246; hg19: chr14-74961032; COSMIC: COSV53143122; COSMIC: COSV53143122;