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

dbSNP: rs879254597

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237158	SCV000294828	pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000586410	SCV000627044	pathogenic	Familial hypercholesterolemia	2025-01-29	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. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 15199436). 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: 251329). 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	Hypercholesterolemia, familial, 1	2019-06-04	criteria provided, single submitter	research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237158	SCV000606172	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research