ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.190+4A>T (rs769446356)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000210581 SCV000263003 uncertain significance Inborn genetic diseases 2014-06-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
LDLR-LOVD, British Heart Foundation RCV000211667 SCV000294504 uncertain significance Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000211667 SCV000484775 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000211667 SCV000599315 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter curation
GeneDx RCV000523458 SCV000617499 likely pathogenic not provided 2018-03-21 criteria provided, single submitter clinical testing The c.190+4 A>T likely pathogenic variant in the LDLR gene has been reported in multiple unrelated patients with FH (Fouchier et al., 2005; Punzalan et al., 2005; Al-Khateeb et al., 2011; Wang et al., 2016). The c.190+4 A>T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a nucleotide position that is conserved through mammals. The c.190+4 A>T variant is predicted to destroy the canonical splice donor site in intron 2 and cause abnormal gene splicing. Finally, other splice site variants in the LDLR gene have been reported in HGMD in association with FH (Stenson et al., 2014).
Invitae RCV000771311 SCV000752427 pathogenic Familial hypercholesterolemia 2019-12-14 criteria provided, single submitter clinical testing This sequence change falls in intron 2 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs769446356, ExAC 0.02%). This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 16250003, 27765764, 15199436, 16205024, 21418584). ClinVar contains an entry for this variant (Variation ID: 225097). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this intronic change results in a reduction in transcripts with this variant compared to wild type and it reduces the amount of surface LDLR and LDL internalization (PMID: 19208450). For these reasons, this variant has been classified as Pathogenic.
Color RCV000771311 SCV000903567 likely pathogenic Familial hypercholesterolemia 2019-09-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000771311 SCV001361873 pathogenic Familial hypercholesterolemia 2019-02-06 criteria provided, single submitter clinical testing Variant summary: The variant, LDLR c.190+4A>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5 splicing donor site. Two predict the variant weakens a 5' donor site. A functional study, Holla_2009, detected aberrant splicing and found the variant to cause a decrease in LDLR at the cell surface (~40% of normal) and internalization (~55% of normal). The variant allele was found at a frequency of 1.8e-05 in 276542 control chromosomes (gnomAD). c.190+4A>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Al-Khateeb_2011, Fouchier_2005, Taylor_2010, Leren_2004, Punzalan_2005). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant three times as likely pathogenic/pathogenic and once as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000211667 SCV001432599 uncertain significance Familial hypercholesterolemia 1 2019-06-05 criteria provided, single submitter research
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211667 SCV000268537 pathogenic Familial hypercholesterolemia 1 2010-03-18 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211667 SCV000606036 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000523458 SCV000925126 pathogenic not provided 2016-07-05 no assertion criteria provided provider interpretation Intronic variant c.190+4A>T in the LDLR gene (NM_000527.4) Given moderate to strong case data and functional studies showing deleterious impact on the protein, we consider this variant likely pathogenic and we feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). We have seen this variant in a person with FH. Testing was done by Ambry. The variant has been seen in at least 6 unrelated cases of FH (not including this patient's family). There is moderate case data, though no segregation has been demonstrated. The c.190+4A>T variant is listed by Ambry in ClinVar, but without any case data. It was reported in the literature by Khateeb et al., 2011 (1 person with FH), by Punzalan et al., 2005 (3 people with FH), and Vandrovcova et al (1 person with FH). It was also reported in Holla et al., 2009 in a Dutch individual reported to have confirmed FH and in Wald et al., 2015 in a 50 year-old with a total cholesterol level of 294 mg/dL and history of myocardial infarction. No other case data was provided. None of the available studies have performed segregation analysis. Holla et al., 2009 performed some functional studies on the c.190+4A>T variant. Semi-quantitative PCR showed a reduced amount of mRNA transcript from the variant allele compared to control cell lines (less than a 42% cut-off). They did not see exon skipping or activation of a cryptic splice site by RT-PCR or activation of a cryptic splice site by Northern Blot for this variant. They speculated that the mutant transcript containing this variant was degraded. Per the Ambry report, this nucleotide position is well conserved in available vertebrate species. The c.190+4A>T variant was reported online in 2 of 60,098 individuals in the Exome Aggregation Consortium dataset (, which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 4/19/2016). Specifically, the variant was observed in 2 of 4297 East Asian individuals. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. An allelic c.190+4A>G variant was also listed in ExAC 1 of 60,098 individuals, specifically in 1 of 4297 East Asian individuals. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). This is especially true for a relatively common disorder like FH.

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