Submissions for variant NM_000527.5(LDLR):c.1811delinsCT (p.Arg604fs)

dbSNP: rs1555806529

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003153681	SCV000627021	pathogenic	Familial hypercholesterolemia	2022-06-13	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with LDLR-related conditions. This sequence change creates a premature translational stop signal (p.Arg604Thrfs*12) 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).
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786160	SCV000924844	likely pathogenic	not provided	2017-08-28	no assertion criteria provided	provider interpretation	p.Arg604Thrfs*12 (c.1811delinsCT) in the LDLR gene (NM_000527.4) - likely pathogenic Given that this variant results in a premature translational stop signal, a known mechanism of disease, we consider this variant likely pathogenic and feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant has not been reported in ClinVar or the medical literature. However, truncating variation in the LDL receptor gene is a known mechanism of disease (Marduel et al, 2010). There is no variation at codon 604 listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is 96x in exomes and 31x in genomes.