ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1133A>C (p.Gln378Pro) (rs730882098)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161980 SCV000189555 not provided not provided no assertion provided in vitro
Fundacion Hipercolesterolemia Familiar RCV000238222 SCV000607563 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Invitae RCV000238222 SCV000627013 likely pathogenic Familial hypercholesterolemia 2017-02-24 criteria provided, single submitter clinical testing This sequence change replaces glutamine with proline at codon 378 of the LDLR protein (p.Gln378Pro). The glutamine residue is weakly conserved and there is a moderate physicochemical difference between glutamine and proline. This variant is present in population databases (rs730882098, ExAC 0.003%). This variant has been reported in several unrelated individuals affected with hypercholesterolemia (PMID: 9664576, 15241806, 19007590, 19446849, 20145306, 22698793, 23375686). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with homozygous familial hypercholesterolemia (PMID: 27784735). This variant is also known as p.Gln357Pro in the literature. ClinVar contains an entry for this variant (Variation ID: 183108). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). In summary, this variant is a rare missense change that has been observed in unrelated individuals with familial hypercholesterolemia. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
LDLR-LOVD, British Heart Foundation RCV000238222 SCV000295241 uncertain significance Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000238222 SCV000540796 uncertain significance Familial hypercholesterolemia 2016-11-05 criteria provided, single submitter clinical testing
Robarts Research Institute,Western University RCV000238222 SCV000484714 likely pathogenic Familial hypercholesterolemia criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000161980 SCV000924846 likely pathogenic not provided 2018-01-09 no assertion criteria provided provider interpretation This variant was identified in a patient with familial hypercholesterolemia. Testing was performed at Invitae. Given the case data and rarity in general population databases we consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Alternate nomenclature for this variant: This variant is also known as p.Gln357Pro. The variant has been seen in at least 8 heterozygotes and 2 compound heterozygotes patients with FH. There is moderate case data and no segregation data. Callis et al. (1998) identified this variant in one patient with FH who was from the UK. Mozas et al. (2004) identified this variant in one patient with FH who was from Spain. Civeira et al. (2008) identified this variant in two female patients with clinical diagnosis of familial combined hyperlipidemia who were recruited from Spain. Senior author is the same as the Mozas paper so cases may be redundant. Guardamanga et al. (2009) reported this variant in a cohort of children recruited from Italy. The authors do not indicate how many patients had this variant. Chmara et al (2010) identified this variant in one patient with FH recruited from Poland. Tichy et al (2012) identified this variant in 1 patient with FH that was Czech. Bertolini et al (2013) identified this variant in 2 Italian patients with FH recruited from Genova, Modena, and and Palermo. The first author on this paper is the same as the last author on the Guardamanga paper and cases may overlap. Sanchez-Hernandez et al (2016) identified this variant two a children with homozygous FH. In one patient, the variant was seen in trans with LDLR p.Ile792Thr and in the other variant it was seen in trans with an unspecified deletion of LDLR. Per the lab report: "Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change." The variant is reported in 1 of 123,076 individuals 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. Specifically, the variant was reported in 1 of 55821 European (NF) individuals (MAF = 0.0008957%). The average coverage at that site in gnomAD is 85x.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000238222 SCV000583794 pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing

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