Submissions for variant NM_018136.5(ASPM):c.7782_7783del (p.Lys2595fs)

dbSNP: rs199422173

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000020796	SCV000192246	pathogenic	Microcephaly 5, primary, autosomal recessive	2013-12-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000365777	SCV000329089	pathogenic	not provided	2022-04-05	criteria provided, single submitter	clinical testing	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: 19770472, 26548919, 29644084, 31853109, 26691732, 23611254, 19028728, 32677750, 31589614, 34426522, 34402213)
Invitae	RCV000365777	SCV000938337	pathogenic	not provided	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys2595Serfs*6) 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). This variant is present in population databases (rs199422173, gnomAD 0.05%). This premature translational stop signal has been observed in individuals with autosomal recessive primary microcephaly (MCPH) (PMID: 19028728, 23611254, 29644084). ClinVar contains an entry for this variant (Variation ID: 21606). For these reasons, this variant has been classified as Pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000020796	SCV000999002	pathogenic	Microcephaly 5, primary, autosomal recessive	2019-09-02	criteria provided, single submitter	clinical testing	A Homozygous two base pair deletion in exon 18 of the ASPM gene that results in a frameshift and premature truncation of the protein 6 amino acids downstream to codon 2595 was detected. The observed variant c.7782_7783del (p.Lys2595SerfsTer6) has not been reported in the 1000 genomes database and has a minor allele frequency of 0.03% in the ExAC database. The in silico prediction of the variant is damaging by MutationTaster2. The reference region is conserved across mammals.
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	RCV000856804	SCV000999370	pathogenic	Microcephaly 1, primary, autosomal recessive		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000365777	SCV001246852	pathogenic	not provided	2019-03-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000020796	SCV002019585	pathogenic	Microcephaly 5, primary, autosomal recessive	2020-10-01	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000020796	SCV002053918	pathogenic	Microcephaly 5, primary, autosomal recessive		criteria provided, single submitter	research
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000020796	SCV002557144	pathogenic	Microcephaly 5, primary, autosomal recessive	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with microcephaly 5, primary (MIM#608716). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 62 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been identified in at least fifteen families with primary microcephaly and classified as pathogenic by diagnosistic laboratories in ClinVar (PMID: 29243349). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics	RCV002513150	SCV003717949	pathogenic	Inborn genetic diseases	2022-02-07	criteria provided, single submitter	clinical testing	The c.7782_7783delGA (p.K2595Sfs*6) alteration, located in exon 18 (coding exon 18) of the ASPM gene, consists of a deletion of 2 nucleotides from position 7782 to 7783, causing a translational frameshift with a predicted alternate stop codon after 6 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Reported in the homozygous state or in trans with a second pathogenic ASPM variant in multiple patients with autosomal recessive primary microcephaly (MCPH)(Nicholas, 2009; Passemard, 2009; Tan, 2014; Kraemer, 2016; Letard, 2017; Okamoto, 2018; Ahmed, 2019; Qi, 2020; Rasool, 2020; Duerinckx, 2021). Based on the available evidence, this alteration is classified as pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000020796	SCV003807616	pathogenic	Microcephaly 5, primary, autosomal recessive	2022-06-03	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 strong, PM3 strong
PreventionGenetics, part of Exact Sciences	RCV003421927	SCV004118415	pathogenic	ASPM-related condition	2023-12-21	criteria provided, single submitter	clinical testing	The ASPM c.7782_7783delGA variant is predicted to result in a frameshift and premature protein termination (p.Lys2595Serfs*6). This variant has been reported, both in the homozygous and compound heterozygous states with a second truncating variant, in several patients affected with primary autosomal recessive microcephaly (Rasool et al. 2020. PubMed ID: 32677750; Nicholas et al. 2009. PubMed ID: 19028728; Tan et al. 2014. PubMed ID: 23611254; Passemard et al. 2016. PubMed ID: 26691732). This variant is reported in 0.046% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in ASPM are expected to be pathogenic. This variant is interpreted as pathogenic.
Genome-Nilou Lab	RCV000020796	SCV004177595	pathogenic	Microcephaly 5, primary, autosomal recessive	2023-04-11	criteria provided, single submitter	clinical testing
OMIM	RCV000020796	SCV000025432	pathogenic	Microcephaly 5, primary, autosomal recessive	2009-07-01	no assertion criteria provided	literature only
GeneReviews	RCV000020796	SCV000041381	not provided	Microcephaly 5, primary, autosomal recessive		no assertion provided	literature only
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000020796	SCV001432335	pathogenic	Microcephaly 5, primary, autosomal recessive		no assertion criteria provided	clinical testing
Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire, Universite Libre de Bruxelles	RCV000020796	SCV001481946	pathogenic	Microcephaly 5, primary, autosomal recessive	2020-01-01	no assertion criteria provided	clinical testing