Submissions for variant NM_000527.5(LDLR):c.2271del (p.Leu759fs)

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211650	SCV000295929	pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
GeneDx	RCV000493493	SCV000582114	pathogenic	not provided	2024-03-24	criteria provided, single submitter	clinical testing	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; Identified in individuals with FH, including in the homozygous or compound heterozygous state in individuals with a clinical diagnosis of HoFH (PMID: 16314194, 21722902, 29576406, 34037665); Not observed at significant frequency in large population cohorts (gnomAD); Also described as Fs736ter743; This variant is associated with the following publications: (PMID: 22089669, 38513336, 28391882, 16314194, 21722902, 35460704, 29576406, 34037665)
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000211650	SCV000583939	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001193182	SCV000627032	pathogenic	Familial hypercholesterolemia	2024-12-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu759Serfs*6) 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 (no rsID available, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 16314194, 22089669). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. ClinVar contains an entry for this variant (Variation ID: 226388). For these reasons, this variant has been classified as Pathogenic.
Iberoamerican FH Network	RCV000211650	SCV000748061	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193182	SCV001361872	pathogenic	Familial hypercholesterolemia	2022-01-31	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.2271delT (p.Leu759SerfsX6) 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 allele was found at a frequency of 8e-06 in 251296 control chromosomes (gnomAD). c.2271delT has been reported in the literature in multiple homozygous and heterozygous individuals affected with Familial Hypercholesterolemia (examples: Robles-Osorio_2006, Hernandez-Flores_2018). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001193182	SCV001734545	pathogenic	Familial hypercholesterolemia	2021-10-12	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 15 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 in Mexico (PMID: 16314194, 21722902, 22089669, 29576406). This variant has been identified in 2/251296 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	RCV002444848	SCV002733276	pathogenic	Cardiovascular phenotype	2023-02-16	criteria provided, single submitter	clinical testing	The c.2271delT pathogenic mutation, located in coding exon 15 of the LDLR gene, results from a deletion of one nucleotide at nucleotide position 2271, causing a translational frameshift with a predicted alternate stop codon (p.L759Sfs*6). This mutation has been detected in individuals with heterozygous and homozygous familial hypercholesterolemia (FH) with co-segregation reported in multiple Mexican families (Robles-Osorio L et al. Arch. Med. Res., 2006 Jan;37:102-8; Vaca G et al. Atherosclerosis, 2011 Oct;218:391-6; Hernández Flores TJ et al. J Clin Lipidol., 2018 Mar;12:693-701). 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.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211650	SCV000268661	pathogenic	Hypercholesterolemia, familial, 1	2010-03-26	no assertion criteria provided	clinical testing