NM_145207.3(AFG2A):c.1586G>A (p.Arg529Gln) AND Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 27, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001029814.4

Allele description [Variation Report for NM_145207.3(AFG2A):c.1586G>A (p.Arg529Gln)]

NM_145207.3(AFG2A):c.1586G>A (p.Arg529Gln)

Gene:

AFG2A:AFG2 AAA ATPase homolog A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4q28.1

Genomic location:

Preferred name:

NM_145207.3(AFG2A):c.1586G>A (p.Arg529Gln)

HGVS:

NC_000004.12:g.122947360G>A
NG_051570.1:g.29291G>A
NM_001317799.2:c.1583G>A
NM_001345856.2:c.1583G>A
NM_145207.3:c.1586G>AMANE SELECT
NP_001304728.1:p.Arg528Gln
NP_001332785.1:p.Arg528Gln
NP_660208.2:p.Arg529Gln
NC_000004.11:g.123868515G>A
NM_145207.2:c.1586G>A
Q8NB90:p.Arg529Gln

Protein change:

R528Q

Links:

UniProtKB: Q8NB90#VAR_075781; dbSNP: rs567175477

NCBI 1000 Genomes Browser:

rs567175477

Molecular consequence:

NM_001317799.2:c.1583G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001345856.2:c.1583G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_145207.3:c.1586G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (NEDHSB)
Synonyms:: NEURODEVELOPMENTAL DISORDER WITH HEARING LOSS, SEIZURES, AND BRAIN ABNORMALITIES
Identifiers:: MONDO: MONDO:0014698; MedGen: C4225276; Orphanet: 457351; OMIM: 616577

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001192597	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	no assertion criteria provided	Likely pathogenic (Jun 25, 2019)	germline	clinical testing
SCV002228041	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 27, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26299366, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001192597

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

no assertion criteria provided

Likely pathogenic
(Jun 25, 2019)

germline

clinical testing

SCV002228041

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 27, 2022)

germline

clinical testing

PubMed (2)
[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

Mutations in SPATA5 Are Associated with Microcephaly, Intellectual Disability, Seizures, and Hearing Loss.

Tanaka AJ, Cho MT, Millan F, Juusola J, Retterer K, Joshi C, Niyazov D, Garnica A, Gratz E, Deardorff M, Wilkins A, Ortiz-Gonzalez X, Mathews K, Panzer K, Brilstra E, van Gassen KL, Volker-Touw CM, van Binsbergen E, Sobreira N, Hamosh A, McKnight D, Monaghan KG, et al.

Am J Hum Genet. 2015 Sep 3;97(3):457-64. doi: 10.1016/j.ajhg.2015.07.014. Epub 2015 Aug 20.

PubMed [citation]

PMID:: 26299366
PMCID:: PMC4564988

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare, SCV001192597.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV002228041.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 529 of the SPATA5 protein (p.Arg529Gln). This variant is present in population databases (rs567175477, gnomAD 0.007%). This missense change has been observed in individual(s) with SPATA5-related epilepsy (PMID: 26299366). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 203523). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SPATA5 protein function. For these reasons, this variant has been classified as Pathogenic.

#	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: Dec 24, 2023

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