NM_018136.5(ASPM):c.3853_3854del (p.Asp1285fs) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Mar 19, 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:: RCV003329243.3

Allele description [Variation Report for NM_018136.5(ASPM):c.3853_3854del (p.Asp1285fs)]

NM_018136.5(ASPM):c.3853_3854del (p.Asp1285fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

1q31.3

Genomic location:

Preferred name:

NM_018136.5(ASPM):c.3853_3854del (p.Asp1285fs)

HGVS:

NC_000001.11:g.197121932_197121933del
NG_015867.1:g.29763_29764del
NM_001206846.2:c.3853_3854del
NM_018136.5:c.3853_3854delMANE SELECT
NP_001193775.1:p.Asp1285fs
NP_060606.3:p.Asp1285fs
NC_000001.10:g.197091061_197091062del
NC_000001.10:g.197091062_197091063del
NM_018136.4:c.3853_3854del
NM_018136.4:c.3853_3854delGA

Protein change:

D1285fs

Links:

dbSNP: rs587783239

NCBI 1000 Genomes Browser:

rs587783239

Molecular consequence:

NM_001206846.2:c.3853_3854del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_018136.5:c.3853_3854del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV004036503	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Mar 19, 2023)	germline	clinical testing	Citation Link,
SCV004293878	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 27, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19028728, 23611254, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004036503

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Mar 19, 2023)

germline

clinical testing

Citation Link,

SCV004293878

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 27, 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	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

The molecular landscape of ASPM mutations in primary microcephaly.

Nicholas AK, Swanson EA, Cox JJ, Karbani G, Malik S, Springell K, Hampshire D, Ahmed M, Bond J, Di Benedetto D, Fichera M, Romano C, Dobyns WB, Woods CG.

J Med Genet. 2009 Apr;46(4):249-53. doi: 10.1136/jmg.2008.062380. Epub 2008 Nov 21.

PubMed [citation]

PMID:: 19028728
PMCID:: PMC2658750

Analysis of ASPM in an ethnically diverse cohort of 400 patient samples: perspectives of the molecular diagnostic laboratory.

Tan CA, del Gaudio D, Dempsey MA, Arndt K, Botes S, Reeder A, Das S.

Clin Genet. 2014 Apr;85(4):353-8. doi: 10.1111/cge.12172. Epub 2013 May 13.

PubMed [citation]

PMID:: 23611254

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV004036503.1

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

Description

Reported previously with a frameshift and a missense ASPM variant in a patient with primary microcephaly, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Tan et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23611254)

#	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, SCV004293878.1

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

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 157813). This premature translational stop signal has been observed in individual(s) with ASPM-related conditions (PMID: 23611254). This variant is present in population databases (rs587783239, gnomAD 0.009%). This sequence change creates a premature translational stop signal (p.Asp1285Serfs*32) 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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