NM_145207.3(AFG2A):c.1343C>T (p.Ser448Leu) AND Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 26, 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:: RCV000193200.8

Allele description [Variation Report for NM_145207.3(AFG2A):c.1343C>T (p.Ser448Leu)]

NM_145207.3(AFG2A):c.1343C>T (p.Ser448Leu)

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.1343C>T (p.Ser448Leu)

HGVS:

NC_000004.12:g.122938134C>T
NG_051570.1:g.20065C>T
NM_001317799.2:c.1340C>T
NM_001345856.2:c.1340C>T
NM_145207.3:c.1343C>TMANE SELECT
NP_001304728.1:p.Ser447Leu
NP_001332785.1:p.Ser447Leu
NP_660208.2:p.Ser448Leu
NC_000004.11:g.123859289C>T
NM_145207.2:c.1343C>T
Q8NB90:p.Ser448Leu

Protein change:

S447L; SER448LEU

Links:

UniProtKB: Q8NB90#VAR_075779; OMIM: 613940.0003; dbSNP: rs766034355

NCBI 1000 Genomes Browser:

rs766034355

Molecular consequence:

NM_001317799.2:c.1340C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001345856.2:c.1340C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_145207.3:c.1343C>T - 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
SCV000246282	OMIM	no assertion criteria provided	Pathogenic (Sep 3, 2015)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001494722	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 26, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26299366, 29389922, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000246282

OMIM

no assertion criteria provided

Pathogenic
(Sep 3, 2015)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV001494722

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 26, 2022)

germline

clinical testing

PubMed (3)
[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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	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

Novel findings with reassessment of exome data: implications for validation testing and interpretation of genomic data.

Gibson KM, Nesbitt A, Cao K, Yu Z, Denenberg E, DeChene E, Guan Q, Bhoj E, Zhou X, Zhang B, Wu C, Dubbs H, Wilkens A, Medne L, Bedoukian E, White PS, Pennington J, Luo M, Conlin L, Monos D, Sarmady M, Marsh E, et al.

Genet Med. 2018 Mar;20(3):329-336. doi: 10.1038/gim.2017.153. Epub 2017 Oct 12. Erratum in: Genet Med. 2018 Nov;20(11):1486. doi: 10.1038/gim.2018.1. Genet Med. 2018 Oct;20(10):1298. doi: 10.1038/gim.2017.264.

PubMed [citation]

PMID:: 29389922

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000246282.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a 4-year-old girl (individual 4) with neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities (NEDHSB; 616577), Tanaka et al. (2015) identified compound heterozygous mutations in the SPATA5 gene: a c.1343C-T transition (c.1343C-T, NM_145207.2), resulting in a ser448-to-leu (S448L) substitution at a highly conserved residue in the first AAA domain, and a c.556C-T transition, resulting in an arg186-to-ter (R186X; 613940.0004) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The c.1343C-T mutation was found at a very low frequency (less than 1 in 10,000) in the ExAC database, but not in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases; c.556C-T was not found in any of the control databases. Functional studies of the variants were not performed.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001494722.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 448 of the SPATA5 protein (p.Ser448Leu). This variant is present in population databases (rs766034355, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of autosomal recessive epilepsy, hearing loss, and intellectual disability syndrome (EHLIDS) (PMID: 26299366, 29389922). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 203527). 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: Sep 29, 2024

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