Submissions for variant NM_174936.4(PCSK9):c.1133_1134delinsAA (p.Cys378Ter)

dbSNP: rs1553137557

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590477	SCV000699982	uncertain significance	not provided	2016-04-28	criteria provided, single submitter	clinical testing	Variant summary: The c.1133_1134delinsAA results in a premature stop codon at amino acid 378, which is predicted to cause a truncated or absent PCSK9 protein. The individual variants are present in the large and broad ExAC cohort in 2/~116,000 control alleles from the general population, which were shown to be in cis in via the NGS reads. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Gain of function mutations in PCSK9 is the commonly know mechanism for disease, and in fact loss-of-function/nonsense mutations may results in lower LDL levels, and thus may have a protective effect (Peterson_2008). Therefore, due to the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000776590	SCV000912205	likely benign	Familial hypercholesterolemia	2018-07-15	criteria provided, single submitter	clinical testing