Submissions for variant NM_000527.5(LDLR):c.622G>T (p.Glu208Ter) (rs879254597)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237158	SCV000294828	pathogenic	Familial hypercholesterolemia 1	2016-03-25	criteria provided, single submitter	literature only
Invitae	RCV000586410	SCV000627044	pathogenic	Familial hypercholesterolemia	2020-07-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu208*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 15199436). ClinVar contains an entry for this variant (Variation ID: 251329). Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586410	SCV000697243	likely pathogenic	Familial hypercholesterolemia	2017-02-03	criteria provided, single submitter	clinical testing	Variant summary: The LDLR c.622G>T (p.Glu208X) variant, alternatively also known as E187X, results in a premature termination codon, predicted to cause a truncated or absent LDLR protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If it escapes NMD, the variant is expected to truncate LDL receptor class A and B repeats, EGF-like domain, cysteine-rich domain and beta-propeller domain (InterPro). Truncations downstream of this position have been classified as pathogenic by our laboratory and others (e.g. p.Cys276X, p.Arg350X, p.Gln384X, etc.). This variant is absent in 120436 control chromosomes from ExAC. In literature, this variant is reported in one index patient with hypercholesterolemia (Leren_2004). Multiple databases have classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia	RCV000237158	SCV001432614	pathogenic	Familial hypercholesterolemia 1	2019-06-04	criteria provided, single submitter	research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000237158	SCV000606172	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research