Submissions for variant NM_000527.5(LDLR):c.2215C>T (p.Gln739Ter) (rs370018159)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237494	SCV000295919	pathogenic	Familial hypercholesterolemia 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute,Western University	RCV000237494	SCV000484732	likely pathogenic	Familial hypercholesterolemia 1		criteria provided, single submitter	clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000237494	SCV000503474	uncertain significance	Familial hypercholesterolemia 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1/FH-Japan
Invitae	RCV000791393	SCV000544653	pathogenic	Familial hypercholesterolemia	2020-03-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal at codon 739 (p.Gln739*) of 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. This particular variant has been reported in the literature in individuals with familial hypercholesterolemia (PMID: 12417285, 20045108, 20538126, 21376320, 23375686). This variant is also known as p.Gln718X in the literature. For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc	RCV000791393	SCV001356940	pathogenic	Familial hypercholesterolemia	2018-12-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000791393	SCV001361871	pathogenic	Familial hypercholesterolemia	2019-10-29	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.2215C>T (p.Gln739X) 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 251316 control chromosomes (gnomAD). c.2215C>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Yu_2002, Robles-Osorio_2006, Romano_2010, Chiou_2010, Pirillo_2017, Kolansky_2008). These data indicate that the variant is very likely to be associated with disease. At least one publication reported that the variant resulted in less than 2% of normal LDLR activity in patient derived skin fibroblasts (Kolansky_2008). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (2x) and as VUS (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia	RCV000237494	SCV001432561	pathogenic	Familial hypercholesterolemia 1	2019-06-04	criteria provided, single submitter	research
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000237494	SCV001653657	pathogenic	Familial hypercholesterolemia 1	2021-05-24	criteria provided, single submitter	clinical testing