Submissions for variant NM_000527.5(LDLR):c.2061dup (p.Asn688fs)

gnomAD frequency: 0.00001  dbSNP: rs137853965

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211582	SCV000295853	pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Athena Diagnostics Inc	RCV000058921	SCV000614006	pathogenic	not provided	2016-11-04	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844732	SCV000711401	pathogenic	Homozygous familial hypercholesterolemia	2019-04-18	criteria provided, single submitter	clinical testing	The p.Asn688Glnfsx29 variant in LDLR has been identified in at least 10 individuals hypercholesterolemia (Graham 2005 Humphries 2006, Hooper 2012, Vandrovcova 2013, Johnston 2015, Abul-Husn 2016, Martin 2016) and has also been reported in ClinVar (Variation ID: 68103). It has been identified in 1/113654 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 688 and leads to a premature termination codon 29 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in familial hypercholesterolemia. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP Criteria applied: PVS1, PS4_Moderate, PM2.
Iberoamerican FH Network	RCV000211582	SCV000748156	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Invitae	RCV000781503	SCV000752425	pathogenic	Familial hypercholesterolemia	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn688Glnfs*29) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is present in population databases (rs751228587, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 16159606, 16389549, 17539906, 22883975, 26046366, 27680772). ClinVar contains an entry for this variant (Variation ID: 68103). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781503	SCV000919584	pathogenic	Familial hypercholesterolemia	2017-11-27	criteria provided, single submitter	clinical testing	Variant summary: The LDLR c.2061dupC (p.Asn688GlnfsX29) variant results in a premature termination codon, predicted to cause a truncated or absent LDLR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/246074 control chromosomes (in gnomAD) at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). The variant was reported in several individuals affected by definite FH (Graham 2005, Humphries 2006, Martin 2016) In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000211582	SCV001432557	pathogenic	Hypercholesterolemia, familial, 1	2019-05-10	criteria provided, single submitter	research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000781503	SCV001435012	pathogenic	Familial hypercholesterolemia	2018-10-15	criteria provided, single submitter	clinical testing	This c.2061dupC (p.Asn688Glnfs*29) variant in exon 14 of the LDLR gene results in an early stop codon. Loss of functions mutations in the LDLR gene are known to be a disease-causing mechanism. This variant has been reported in one patient with familial hypercholesterolaemia (PMID: 16389549). It has been reported at low allelic frequencies in the population database gnomAD (http://gnomad.broadinstitute.org/variant/19-11231118-T-TC). Therefore, the c.2061dupC (p.Asn688Glnfs*29) variant in the LDLR gene has been classified as a pathogenic variant.
Color Diagnostics, LLC DBA Color Health	RCV000781503	SCV001733660	pathogenic	Familial hypercholesterolemia	2020-12-08	criteria provided, single submitter	clinical testing	This variant inserts one nucleotide in exon 14 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 16159606, 16389549, 17539906, 22883975, 26046366, 27680772). This variant has been identified in 1/251240 chromosomes 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.
Ambry Genetics	RCV002415518	SCV002725605	pathogenic	Cardiovascular phenotype	2022-05-12	criteria provided, single submitter	clinical testing	The c.2061dupC pathogenic mutation, located in coding exon 14 of the LDLR gene, results from a duplication of C at nucleotide position 2061, causing a translational frameshift with a predicted alternate stop codon (p.N688Qfs*29). This variant has been identified in multiple individuals with definite familial hypercholesterolemia (FH) or possible FH (Graham CA et al. Atherosclerosis, 2005 Oct;182:331-40; Humphries SE et al. J Mol Med (Berl), 2006 Mar;84:203-14; Taylor A et al. Clin Genet, 2007 Jun;71:561-8; Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4; Faiz F et al. Atherosclerosis, 2013 Oct;230:249-55). 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.
Revvity Omics, Revvity	RCV000211582	SCV003827080	pathogenic	Hypercholesterolemia, familial, 1	2022-07-06	criteria provided, single submitter	clinical testing
SNPedia	RCV000058921	SCV000090442	not provided	not provided		no assertion provided	not provided
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211582	SCV000268657	pathogenic	Hypercholesterolemia, familial, 1	2008-08-25	no assertion criteria provided	clinical testing