Submissions for variant NM_000527.5(LDLR):c.2469_2470insTTTTTTTTTTTTTTTTTNNNNNNNNNNTTAGCCAGGATGGTCTCGATCTCCTGACCTCGTGATCCGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAAGCGTGAGCCACCGCGCCCGGCCAACAGCATCAACTTT (p.Asp824delinsPhePhePhePhePheXaaXaaXaaXaaLeuAlaArgMetValSerIleSerTer)

dbSNP: rs2147287083

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001381977	SCV001580554	pathogenic	Familial hypercholesterolemia	2020-09-04	criteria provided, single submitter	clinical testing	This variant disrupts the C-terminus of the LDLR protein. Other variant(s) that disrupt this region (p.Ser849*) have been determined to be pathogenic (PMID: 26892515, 11933210, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has not been reported in the literature in individuals with LDLR-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 17 of the LDLR gene (c.2469_2470ins?), causing a frameshift at codon 824 (p.Asp824fs). 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. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to disrupt protein function (PMID: 19763152, 20307669, 22406018). However the effect of this particular variant is unknown. For these reasons, this variant has been classified as Pathogenic.