Submissions for variant NM_000527.5(LDLR):c.191-2A>G

dbSNP: rs544203837

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211652	SCV000294510	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000211652	SCV000484774	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Fundacion Hipercolesterolemia Familiar	RCV000211652	SCV000607429	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Invitae	RCV000799814	SCV000939495	pathogenic	Familial hypercholesterolemia	2023-05-01	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. Studies have shown that disruption of this splice site results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 19208450). ClinVar contains an entry for this variant (Variation ID: 226306). This variant is also known as In 2 A-2G and IVS2-2A>G. Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 9259195, 10735632, 21475731, 22390909, 27765764; Invitae). This sequence change affects an acceptor splice site in intron 2 of the LDLR gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product.
Ambry Genetics	RCV002408913	SCV002719977	pathogenic	Cardiovascular phenotype	2022-02-09	criteria provided, single submitter	clinical testing	The c.191-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 3 in the LDLR gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This mutation has been reported in several familial hypercholesterolemia (FH) cohorts (Day IN et al. Hum Mutat, 1997;10:116-27; Lombardi MP et al. Clin Genet, 2000 Feb;57:116-24; Wang J et al. Arterioscler Thromb Vasc Biol, 2016 12;36:2439-2445; Dron JS et al. BMC Med Genomics, 2020 02;13:23; Sturm AC et al. JAMA Cardiol, 2021 08;6:902-909). Additionally, a functional study showed the expression of an alternate transcript (Holla ØL et al. Mol Genet Metab, 2009 Apr;96:245-52). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211652	SCV000268540	pathogenic	Hypercholesterolemia, familial, 1	2012-03-22	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211652	SCV000606040	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000211652	SCV000733813	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001699013	SCV001921193	pathogenic	not provided		no assertion criteria provided	clinical testing