Submissions for variant NM_000527.5(LDLR):c.2312-3C>A

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211656	SCV000295947	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000211656	SCV000588653	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586092	SCV000697226	pathogenic	Familial hypercholesterolemia	2016-09-06	criteria provided, single submitter	clinical testing	Variant summary: The LDLR c.2312-3C>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant, and 5/5 splicing algorithms predict this variant to reduce the splice acceptor site strength. LDLR residual activity on stimulated T-lymphocytes from multiple heterozygous patients were approximately 50% of normal activity, suggesting that this variant results in little to no residual activity. This variant was not found in large and broad populations from ExAC. It has been reported as one of the common pathogenic variants that causes FH. Furthermore, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	RCV000211656	SCV000987039	pathogenic	Hypercholesterolemia, familial, 1	2018-10-22	criteria provided, single submitter	clinical testing	The mutation leads to a change in the splice acceptor in intron 15 of the LDLR gene. It has already been described in the literature, detected in patients with familial hypercholesterolemia, and associated with elevated cholesterol and LDL-C levels. In in vitro models, the mutation leads to almost complete loss of LDL receptor activity. We observed this mutation in a patient with TC up to 520 mg/dl and LDL-C approx 420 mg/dl at the age of 45 years. PMID: 11317362, 21865347
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000211656	SCV001653659	likely pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing	Reduced activity, in stimulated T-lymphocytes and EBV-transformed B-lymphocytes.
GeneDx	RCV001553274	SCV001774118	pathogenic	not provided	2023-05-22	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate skipping of exon 16 and reduced LDLR activity (PMID: 11317362, 21865347); Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); This variant is associated with the following publications: (PMID: 11317362, 21865347, 25525159, 18718593, 11668640, 30710474, 32331935, 32994617, 12628589, 12417285, 14624402, 16627557, 16115486, 28965616, 31345425, 31491741, 34040191, 33740630, 34756585, 34297352)
Ambry Genetics	RCV002426992	SCV002731831	pathogenic	Cardiovascular phenotype	2024-09-03	criteria provided, single submitter	clinical testing	The c.2312-3C>A intronic variant results from a C to A substitution 3 nucleotides upstream from coding exon 16 in the LDLR gene. This alteration has been detected in numerous individuals with familial hypercholesterolemia (FH) from a variety of ethnic backgrounds, and segregation with disease has been reported in multiple families (Liguori R et al. Hum. Mutat., 2001 May;17:433; García-García AB et al. Hum. Mutat., 2001 Nov;18:458-9; Pisciotta L et al. Atherosclerosis, 2005 Sep;182:153-9; Miyake Y et al. Atherosclerosis, 2009 Mar;203:153-60; Rubba P et al. Eur J Prev Cardiol, 2017 Jul;24:1051-1059). In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site. Functional studies have demonstrated skipping of exon 16, with the in-frame deletion of 26 amino acids, and reduced LDLR activity to approximately 50% of wild-type (Romano M et al. Atherosclerosis, 2010 Jun;210:493-6). This nucleotide position is highly conserved in available vertebrate species. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000586092	SCV003443109	pathogenic	Familial hypercholesterolemia	2023-07-20	criteria provided, single submitter	clinical testing	This sequence change falls in intron 15 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with familial hypercholesterolemia (PMID: 11317362, 31491741). ClinVar contains an entry for this variant (Variation ID: 226391). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
All of Us Research Program, National Institutes of Health	RCV000211656	SCV005427654	pathogenic	Hypercholesterolemia, familial, 1	2024-08-23	criteria provided, single submitter	clinical testing	This variant causes a C to A nucleotide substitution at the -3 position of intron 15 of the LDLR gene. Functional RNA studies have shown that this variant causes in-frame skipping of exon 16, resulting in the loss of the 26-amino acid transmembrane functional domain (PMID: 11317362). In vitro functional studies using EBV-transformed B-lymphocytes have shown that this variant causes a significant reduction in residual LDLR activity (PMID: 20045108, 21865347). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 11317362, 11668640, 12417285, 14624402, 16115486, 18718593, 25014035, 28353356, 28179607, 30710474, 32331935, 33740630). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 11317362, 11668640, 14624402, 16115486). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211656	SCV000268664	pathogenic	Hypercholesterolemia, familial, 1	2009-07-24	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211656	SCV000606631	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000211656	SCV001432564	uncertain significance	Hypercholesterolemia, familial, 1	2019-06-17	flagged submission	research