Submissions for variant NM_000527.5(LDLR):c.694+1G>C

dbSNP: rs879254646

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002233349	SCV000829708	pathogenic	Familial hypercholesterolemia	2018-04-16	criteria provided, single submitter	clinical testing	Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). Other substitutions at this nucleotide (c.694+1G>A, c.694+1G>T) have been reported in individuals affected with hypercholesterolemia (PMID: 16542394, 20809525). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with LDLR-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 4 of the LDLR gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic.
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000700931	SCV001653606	pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing