Submissions for variant NM_000527.5(LDLR):c.680_682delinsCGGTATGGACTGCA (p.Asp227fs)

dbSNP: rs879254637

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484687	SCV000572556	pathogenic	not provided	2025-01-07	criteria provided, single submitter	clinical testing	Very similar insertion/deletion (c.679del4ins15; originally reported as 676insACGGTATGGACTGCAdelGACG), has been identified in one individual with primary hypercholesterolemia in the published literature (PMID: 11462246); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.Asp207AlafsX; This variant is associated with the following publications: (PMID: 17539906, 31447099, 32770674, 27535533, 11462246, 28161202)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193785	SCV001362896	pathogenic	Familial hypercholesterolemia	2019-08-19	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.680_682delins14 (c.680_682delinsCGGTATGGACTGCA, p.Asp227AlafsX42) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 248472 control chromosomes (gnomAD) but has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Marmontel_2018, Taylor_2007, Wintjens_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV002367651	SCV002666305	pathogenic	Cardiovascular phenotype	2018-08-09	criteria provided, single submitter	clinical testing	The c.680_682delACGins14 pathogenic mutation, located in coding exon 4 of the LDLR gene, results from the deletion of 3 nucleotides and insertion of 14 nucleotides (CGGTATGGACTGCA) at positions 680 to 682, causing a translational frameshift with a predicted alternate stop codon (p.D227Afs*42). This mutation has been previously reported in two familial hypercholesterolemia cohorts (Taylor A et al. Clin. Genet. 2007:71(6):561-8; Minicocci I et al. Pediatr. 2017;183:100-107). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484687	SCV004219995	pathogenic	not provided	2023-06-07	criteria provided, single submitter	clinical testing	The LDLR c.680_682delins14 (p.Asp227Alafs*42) variant alters the translational reading frame of the LDLR mRNA and causes the premature termination of LDLR protein synthesis. This variant has been reported in the published literature in individuals with definite or suspected familial hypercholesterolemia (PMIDs: 17539906 (2007), 26802169 (2016), 28161202 (2017), 29572815 (2018), and 32770674 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
All of Us Research Program, National Institutes of Health	RCV004806368	SCV005426463	pathogenic	Hypercholesterolemia, familial, 1	2024-04-16	criteria provided, single submitter	clinical testing	This variant deletes 3 nucleotides and inserts 14 nucleotides in exon 4 of the LDLR type A repeat 5 of the LDLR gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 26802169, 28161202, 29888156, 29572815, 32770674). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.