NM_018136.5(ASPM):c.9190C>T (p.Arg3064Ter) AND not provided

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Jun 11, 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:: RCV000219573.8

Allele description [Variation Report for NM_018136.5(ASPM):c.9190C>T (p.Arg3064Ter)]

NM_018136.5(ASPM):c.9190C>T (p.Arg3064Ter)

Gene:

ASPM:assembly factor for spindle microtubules [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q31.3

Genomic location:

Preferred name:

NM_018136.5(ASPM):c.9190C>T (p.Arg3064Ter)

HGVS:

NC_000001.11:g.197093156G>A
NG_015867.1:g.58539C>T
NM_001206846.2:c.4435C>T
NM_018136.5:c.9190C>TMANE SELECT
NP_001193775.1:p.Arg1479Ter
NP_060606.3:p.Arg3064Ter
NC_000001.10:g.197062286G>A
NM_018136.4:c.9190C>T

Protein change:

R1479*

Links:

dbSNP: rs199422185

NCBI 1000 Genomes Browser:

rs199422185

Molecular consequence:

NM_001206846.2:c.4435C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_018136.5:c.9190C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000279579	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Apr 14, 2017)	germline	clinical testing	Citation Link,
SCV001952201	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001964634	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002033900	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV003523988	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 11, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 14574646, 32404165, 32677750, 19028728, 23611254, 28492532

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Summary from all submissions

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

Citations

PubMed

Protein-truncating mutations in ASPM cause variable reduction in brain size.

Bond J, Scott S, Hampshire DJ, Springell K, Corry P, Abramowicz MJ, Mochida GH, Hennekam RC, Maher ER, Fryns JP, Alswaid A, Jafri H, Rashid Y, Mubaidin A, Walsh CA, Roberts E, Woods CG.

Am J Hum Genet. 2003 Nov;73(5):1170-7. Epub 2003 Oct 21.

PubMed [citation]

PMID:: 14574646
PMCID:: PMC1180496

Molecular diagnosis in recessive pediatric neurogenetic disease can help reduce disease recurrence in families.

Issa MY, Chechlacz Z, Stanley V, George RD, McEvoy-Venneri J, Belandres D, Elbendary HM, Gaber KR, Nabil A, Abdel-Hamid MS, Zaki MS, Gleeson JG.

BMC Med Genomics. 2020 May 13;13(1):68. doi: 10.1186/s12920-020-0714-1.

PubMed [citation]

PMID:: 32404165
PMCID:: PMC7218834

See all PubMed Citations (6)

Details of each submission

From GeneDx, SCV000279579.9

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

Description

The R3064X nonsense variant in the ASPM gene has been reported previously in association with primary autosomal recessive microcephaly (MCPH) (Bond et al., 2003). The R3064X variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.

#	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 Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001952201.1

#	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 Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001964634.1

#	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 Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV002033900.1

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003523988.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 21621). This premature translational stop signal has been observed in individual(s) with clinical features of ASPM-related conditions (PMID: 14574646, 32404165, 32677750). This variant is present in population databases (rs199422185, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Arg3064*) in the ASPM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ASPM are known to be pathogenic (PMID: 19028728, 23611254).

#	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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