Submissions for variant NM_020987.5(ANK3):c.3376A>G (p.Ile1126Val)

dbSNP: rs1057524244

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000432825	SCV000534973	uncertain significance	not provided	2016-12-19	criteria provided, single submitter	clinical testing	The I1126V variant in the ANK3 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The I1126V variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I1126V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In addition, this substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret I1126V as a variant of uncertain significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786714	SCV005399262	uncertain significance	Intellectual disability-hypotonia-spasticity-sleep disorder syndrome	2019-08-28	criteria provided, single submitter	clinical testing	A heterozygous missense variant was identified, NM_020987.4(ANK3):c.3376A>G in exon 29 of 44 of the ANK3 gene. This substitution is predicted to create a minor amino acid change from isoleucine to valine at position 1126 of the protein, NP_066267.2(ANK3):p.(Ile1126Val). The valine at this position is located in a region of moderate conservation (100 vertebrates, UCSC), within the ZU5 1 motif (PDB, UniProt). In silico software predictions of the pathogenicity of this variant are conflicting (PolyPhen, SIFT, CADD, MutationTaster). The variant is not present in the gnomAD population database. Alternative changes to methionine and threonine at the same residue have been reported in the gnomAD database at a frequency of 0.005% each in the East Asian population. The variant has been previously reported as a VUS. Analysis of parental samples indicated that this variant was maternally inherited. Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS).