Submissions for variant NM_000527.5(LDLR):c.81C>A (p.Cys27Ter)

dbSNP: rs2228671

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237744	SCV000294453	pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000237744	SCV000503099	pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 2 , family member = 1 with co-segregation
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237744	SCV000583626	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing	ACMG Guidelines: Likely Pathogenic (ii)
Fundacion Hipercolesterolemia Familiar	RCV000237744	SCV000607411	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000775250	SCV000909508	pathogenic	Familial hypercholesterolemia	2018-08-20	criteria provided, single submitter	clinical testing	Pathogenic variant based on current evidence: This variant changes a single nucleotide in exon 2 of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with familial hypercholesterolemia in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Loss-of-function truncation variants in the LDLR gene are known to be pathogenic (PMID: 20809525). Based on available evidence, this variant is classified as Pathogenic.
Invitae	RCV000775250	SCV001587271	pathogenic	Familial hypercholesterolemia	2023-03-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 251009). This variant is also known as C6X. This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 15556094, 23375686). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys27*) 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).
Ambry Genetics	RCV002429161	SCV002680118	pathogenic	Cardiovascular phenotype	2018-01-15	criteria provided, single submitter	clinical testing	The p.C27* pathogenic mutation (also known as c.81C>A), located in coding exon 2 of the LDLR gene, results from a C to A substitution at nucleotide position 81. This changes the amino acid from a cysteine to a stop codon within coding exon 2, and is located in the ligand-binding domain. This alteration has been reported in hypercholesterolemia cohorts (Laurie AD et al. Atheroscler Suppl, 2004 Dec;5:13-5; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8). 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.