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

Total submissions: 7

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