ClinVar Miner

Submissions for variant NM_015627.3(LDLRAP1):c.649G>T (p.Glu217Ter)

dbSNP: rs2044402416
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences RCV001292554 SCV001430577 pathogenic Autosomal recessive inheritance 2020-05-04 criteria provided, single submitter clinical testing The LDLR adaptor protein 1 (LDLRAP1 protein; GenBank Accession no. NP_056442) is required for receptor-mediated endocytosis of LDL and mutations in this gene (LDLRAP1, MIM 605747) result in an autosomal recessive form of FH (autosomal recessive hypercholesterolemia, ARH; Online Mendelian Inheritance in Man [OMIM] catalog number 603813) (Khachadurian 1973, Garcia 2001). Different mutations in LDLRAP1 gene have been reported, which lead to ARH disease (Fellin 2015). According to currently available information on The Human Gene Mutation Database (HMGD; http://www.hgmd.cf.ac.uk/ac/gene.php?gene=ARH), 26 pathogenic variants in the coding sequence of LDLRAP1 have been reported. A recent report by Rodriguez-Jimenez et al, 2019 described that in LDLRAP1:c.1A>G lymphocytes reduced fluorescent LDL uptake compared to control lymphocytes can be seen. Similarly, reduced LDL uptake have also demonstrated in by lymphocytes of 28 ARH patients and five LDLRAP1 variants (Thedrez 2016). The LDLRAP1 variant c.649G>T generates a new stop codon in codon 217 in exon 7 just downstream of the LDL-C Clathrin Box domain; based upon privous studies and functional studies, the novel variant, c.649G>T, is a pathogenic one.
Labcorp Genetics (formerly Invitae), Labcorp RCV005094235 SCV005742439 pathogenic Hypercholesterolemia, familial, 4 2024-11-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu217*) in the LDLRAP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLRAP1 are known to be pathogenic (PMID: 11326085, 12464675). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hypercholesterolemia (PMID: 34629743). ClinVar contains an entry for this variant (Variation ID: 981055). For these reasons, this variant has been classified as Pathogenic.

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