Submissions for variant NM_000527.5(LDLR):c.2459_2460insTGATGAGGATGGACAGAGAAGGTCTCTGATAAGATTTGTTTCTTTTGCCTCTCCCCTCTCCCCTCTCCCCNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAGAACATCAACAG (p.Ser820_Ile821insAspGluAspGlyGlnArgArgSerLeuIleArgPheValSerPheAlaSerProLeuSerProLeuProXaaXaaXaaXaaLysLysLysLysLysLysLysLysLysLysLysLysAsnIleAsnSer)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002816138	SCV003207051	pathogenic	Familial hypercholesterolemia	2022-06-10	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with LDLR-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 17 of the LDLR gene (c.2459_2460ins?), causing a frameshift at codon 820 (p.Ser820fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018) and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073).