Submissions for variant NM_001083961.2(WDR62):c.1043+3A>G

gnomAD frequency: 0.00009  dbSNP: rs587784541

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000147909	SCV000195400	uncertain significance	Microcephaly 2, primary, autosomal recessive, with or without cortical malformations	2014-05-28	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000344609	SCV000341474	uncertain significance	not provided	2016-05-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000344609	SCV001334530	uncertain significance	not provided	2020-03-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000344609	SCV001757734	likely pathogenic	not provided	2020-12-16	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV000344609	SCV002143525	likely pathogenic	not provided	2023-07-07	criteria provided, single submitter	clinical testing	This sequence change falls in intron 8 of the WDR62 gene. It does not directly change the encoded amino acid sequence of the WDR62 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs587784541, gnomAD 0.01%). This variant has been observed in individual(s) with primary microcephaly (PMID: 34402213). 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: 160243). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000147909	SCV002768184	pathogenic	Microcephaly 2, primary, autosomal recessive, with or without cortical malformations	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 primary microcephaly 2, with or without cortical malformations (MIM#604317). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 13 heterozygotes, 0 homozygotes). (SP) 0705 - No comparable splice site variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in a homozygous state in two individuals within the DECIPHER cohort with microcephaly, intellectual disability and seizures; one of individuals also had polymicrogyria. At least two affected individuals were also identified by diagnostics laboratories in ClinVar, with one laboratory classifying the variant as likely pathogenic and the other as a variant of uncertain significance. Most recently, the variant has been reported in a homozygous state and a compound heterozygous state in two individuals with microcephaly, intellectual disability and seizures (PMID: 34402213). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Revvity Omics, Revvity	RCV000147909	SCV003823727	uncertain significance	Microcephaly 2, primary, autosomal recessive, with or without cortical malformations	2021-01-08	criteria provided, single submitter	clinical testing
Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire, Universite Libre de Bruxelles	RCV000147909	SCV001481958	pathogenic	Microcephaly 2, primary, autosomal recessive, with or without cortical malformations	2020-01-01	no assertion criteria provided	clinical testing