Submissions for variant NM_001001331.4(ATP2B2):c.1369G>A (p.Glu457Lys)

dbSNP: rs1064795322

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484854	SCV000571013	likely pathogenic	not provided	2016-07-25	criteria provided, single submitter	clinical testing	The E412K variant in the ATP2B2 gene has not been reported previously as a pathogenic variant in humans, nor as a benign variant, to our knowledge. However, hearing loss studies utilizing murine models have demonstrated that E412K heterozygous mice have progressive hearing loss with cochlear degeneration and E412K homozygous mice have severe hearing loss shortly after birth, degeneration of both the cochlea and saccule, and abnormal movements (Takahashi et al., 1999). The E412K 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 E412K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. While in silico analysis predicts this variant is probably damaging to the protein structure/function, immunohistochemical staining of outer and inner hair cells derived from E412K homozygous mice, showed faint or absent ATP2B2 in stereocilia and cell bodies of the inner hair cells, and an abnormally rounded inner hair cell shape (Takahashi et al., 1999). Therefore, we interpret E412K as a likely pathogenic variant.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335365	SCV004046021	likely pathogenic	ATP2B2-related disorder		criteria provided, single submitter	clinical testing	This variant has not been previously reported or functionally characterized in the literature to our knowledge. The ATP2B2 gene is constrained against variation (Z-score= 4.55 and pLI=1), which suggests it is intolerant to variation. The c.1369G>A (p.Glu457Lys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. The c.1369G>A (p.Glu457Lys) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.1369G>A (p.Glu457Lys) variant is classified as Likely Pathogenic.