ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1705+1G>A (rs875989926)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000211580 SCV000295591 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000211580 SCV000599381 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter curation
Iberoamerican FH Network RCV000211580 SCV000748114 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Invitae RCV000211580 SCV000752424 pathogenic Familial hypercholesterolemia 2018-01-18 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 11 of the LDLR gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant was observed in individuals affected with familial hypercholesterolemia (PMID: 10532689, 20145306, 19208450, 17406740).   ClinVar contains an entry for this variant (Variation ID: 226367). Experimental studies have shown that this chance results in exon skipping and in reduced LDLR activity (PMID: 19208450). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). For these reasons, this variant has been classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000211580 SCV000839976 likely pathogenic Familial hypercholesterolemia 2018-03-27 criteria provided, single submitter clinical testing The c.1705+1G>A variant in the LDLR gene disrupts the canonical splice donor site in intron 11 and is predicted to result in abnormal mRNA splicing. This variant has been reported in multiple unrelated individuals with familial hypercholesterolemia (PMID: 10532689, 19318025, 20145306). The c.1705+1G>A variant in the LDLR gene is classified as likely pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000825623 SCV000966975 pathogenic Familial hypercholesterolemia - homozygous 2018-06-11 criteria provided, single submitter clinical testing The c.1705+1G>A variant in LDLR has been reported in 6 Caucasian individuals wit h hypercholesterolemia (Jensen 1999, Chmara 2010, Sharifi 2016) and was absent f rom large population studies. This variant occurs in the invariant region (+/- 1 ,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Furthermore, other variants in the sam e splice consensus sequence have been reported in individuals with hypercholeste rolemia (c.1705+1G>C, c.1705+1G>T). In vitro functional studies of the c.1705+1G >T and the c.1705+1G>A variants provide some evidence of abnormal splicing (R?dn ingen 1999; Holla 2009). In summary, this variant meets criteria to be classifie d as pathogenic for hypercholesterolemia in an autosomal dominant manner based u pon proband counts, absence from controls, and functional impact. ACMG/AMP Crite ria applied: PVS1; PM2; PS4_Supporting; PS3_Supporting.
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211580 SCV000268630 pathogenic Familial hypercholesterolemia 2011-06-01 no assertion criteria provided clinical testing

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