NM_194279.4(ISCA2):c.229G>A (p.Gly77Ser) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 28, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000255374.17

Allele description [Variation Report for NM_194279.4(ISCA2):c.229G>A (p.Gly77Ser)]

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

Gene:

ISCA2:iron-sulfur cluster assembly 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q24.3

Genomic location:

Preferred name:

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

HGVS:

NC_000014.9:g.74494329G>A
NG_007117.1:g.4053C>T
NG_033074.1:g.5610G>A
NM_001272007.2:c.174+177G>A
NM_194279.4:c.229G>AMANE SELECT
NP_919255.2:p.Gly77Ser
NP_919255.2:p.Gly77Ser
NC_000014.8:g.74961032G>A
NM_194279.3:c.229G>A
Q86U28:p.Gly77Ser

Protein change:

G77S; GLY77SER

Links:

UniProtKB: Q86U28#VAR_073794; OMIM: 615317.0001; dbSNP: rs730882246

NCBI 1000 Genomes Browser:

rs730882246

Molecular consequence:

NM_001272007.2:c.174+177G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_194279.4:c.229G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000322178	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 7, 2020)	germline	clinical testing	Citation Link,
SCV001578006	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 28, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25558065, 29122497, 29297947, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000322178

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Oct 7, 2020)

germline

clinical testing

Citation Link,

SCV001578006

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 28, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.

Alazami AM, Patel N, Shamseldin HE, Anazi S, Al-Dosari MS, Alzahrani F, Hijazi H, Alshammari M, Aldahmesh MA, Salih MA, Faqeih E, Alhashem A, Bashiri FA, Al-Owain M, Kentab AY, Sogaty S, Al Tala S, Temsah MH, Tulbah M, Aljelaify RF, Alshahwan SA, Seidahmed MZ, et al.

Cell Rep. 2015 Jan 13;10(2):148-61. doi: 10.1016/j.celrep.2014.12.015. Epub 2014 Dec 31.

PubMed [citation]

PMID:: 25558065

Further delineation of the phenotypic spectrum of ISCA2 defect: A report of ten new cases.

Alfadhel M, Nashabat M, Alrifai MT, Alshaalan H, Al Mutairi F, Al-Shahrani SA, Plecko B, Almass R, Alsagob M, Almutairi FB, Al-Rumayyan A, Al-Twaijri W, Al-Owain M, Taylor RW, Kaya N.

Eur J Paediatr Neurol. 2018 Jan;22(1):46-55. doi: 10.1016/j.ejpn.2017.10.003. Epub 2017 Oct 16.

PubMed [citation]

PMID:: 29122497

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000322178.7

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

Description

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)

#	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 Invitae, SCV001578006.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	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

Last Updated: Jul 7, 2024

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