Submissions for variant NM_000527.5(LDLR):c.1359-31_1359-23delinsCGGCT

dbSNP: rs879254876

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238072	SCV004022444	uncertain significance	Hypercholesterolemia, familial, 1	2023-03-20	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1359-31_1359-23delinsCGGCT variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS3_supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: - PM2: This variant is absent from gnomAD (gnomAD v2.1.1). - PP4: Variant meets PM2. Identified in 1 FH case from PMID: 8872473 meeting Simon-Broome criteria of possible FH , after alternative causes of high cholesterol were excluded. - PS3: Level 3 assay: PMID 8872473: Heterozygous patient's Epstein-Barr virus transformed lymphoblasts, RNA assays; Heterologous cells (COS), RNA assays: Retention of intron 9 (p.Ser453Argfs*2) ---- functional study is consistent with damaging effect.
LDLR-LOVD, British Heart Foundation	RCV000238072	SCV000295386	pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000238072	SCV000599371	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	curation
Color Diagnostics, LLC DBA Color Health	RCV001525939	SCV001736158	uncertain significance	Familial hypercholesterolemia	2023-10-25	criteria provided, single submitter	clinical testing	This variant deletes 9 nucleotides and inserts 5 nucleotides, CGGCT, in intron 9 of the LDLR gene. An RNA study using patient-derived lymphoblasts and a minigene assay have shown that this variant causes a retention of intron 9 sequence in mRNA and utilization of cryptic acceptor sites in exon 10, resulting in a frameshift and premature translation stop signal (PMID: 8872473). This variant has been reported in one individual affected with familial hypercholesterolemia (PMID: 8872473). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002379066	SCV002690265	likely pathogenic	Cardiovascular phenotype	2018-10-18	criteria provided, single submitter	clinical testing	The c.1359-31_1359-23delGCGCTGATGinsCGGCT intronic variant, located in intron 9 of the LDLR gene, results from an in-frame from the deletion of 9 nucleotides and the insertion of 5 nucleotides at nucleotide position 1359. This alteration has been reported in an individual with familial hypercholesterolemia (FH), and RNA studies have demonstrated that this alteration leads to the retention of intron 9 and incorporation of a premature stop codon (Webb JC et al. Hum. Mol. Genet., 1996 Sep;5:1325-31). These nucleotide positions are not well conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238072	SCV000606406	benign	Hypercholesterolemia, familial, 1		no assertion criteria provided	research