NM_145207.3(AFG2A):c.394C>T (p.Gln132Ter) AND Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Sep 21, 2021
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:: RCV000578372.11

Allele description

NM_145207.3(AFG2A):c.394C>T (p.Gln132Ter)

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.394C>T (p.Gln132Ter)

HGVS:

NC_000004.12:g.122929145C>T
NG_051570.1:g.11076C>T
NM_001317799.2:c.391C>T
NM_001345856.2:c.391C>T
NM_145207.3:c.394C>TMANE SELECT
NP_001304728.1:p.Gln131Ter
NP_001332785.1:p.Gln131Ter
NP_660208.2:p.Gln132Ter
NC_000004.11:g.123850300C>T
NM_145207.2:c.394C>T

Protein change:

Q131*

Links:

dbSNP: rs1220351376

NCBI 1000 Genomes Browser:

rs1220351376

Molecular consequence:

NM_001317799.2:c.391C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001345856.2:c.391C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_145207.3:c.394C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

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
SCV000680390	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Sep 8, 2017)	maternal	clinical testing	Citation Link,
SCV002021915	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 17, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002147016	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 21, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26299366, 29343804, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000680390

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

criteria provided, single submitter

(Classification criteria August 2017)

Pathogenic
(Sep 8, 2017)

maternal

clinical testing

Citation Link,

SCV002021915

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 17, 2019)

germline

clinical testing

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

SCV002147016

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 21, 2021)

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	maternal	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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

See all PubMed Citations (4)

Details of each submission

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV000680390.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	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	maternal	yes	1	blood	not provided		1	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002021915.3

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

#	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

From Invitae, SCV002147016.2

#	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 creates a premature translational stop signal (p.Gln132*) in the SPATA5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPATA5 are known to be pathogenic (PMID: 26299366). This variant is not present in population databases (ExAC no frequency). This premature translational stop signal has been observed in individual(s) with SPATA5-related conditions (PMID: 29343804). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 488607). 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: Jun 17, 2024

ClinVar

Relating variation to medicine