ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.680_681delAC (p.Asp227Glyfs) (rs387906305)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000003929 SCV000294896 pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000003929 SCV000484796 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000003929 SCV000503211 pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 , family member = 1 with co-segregation
Athena Diagnostics Inc RCV000517763 SCV000614009 pathogenic not provided 2017-06-07 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844736 SCV000713116 pathogenic Homozygous familial hypercholesterolemia 2019-05-08 criteria provided, single submitter clinical testing The p.Asp227fs variant in LDLR has been reported in at least 9 individuals with hypercholesterolemia (Gudnason 1993, Graham 1999, Bunn 2002, Dedoussis 2004, Martin 2016) and has also been reported in ClinVar (Variation ID #3731). This variant has also been identified in 1/110684 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs387906305). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 227 and leads to a premature termination codon 12 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in familial hypercholesterolemia (FH). In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dominant manner based upon the predicted impact to the protein, presence in multiple affected individuals and low frequency in controls. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate.
Invitae RCV001201362 SCV000752414 pathogenic Familial hypercholesterolemia 2019-05-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asp227Glyfs*12) in the LDLR gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with familial hypercholesterolemia (FH) (PMID: 8093663, 14974088, 27765764, 11857755). This variant is also known as 679-680delAC and p.D206fs in the literature. ClinVar contains an entry for this variant (Variation ID: 3731). 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 RCV000003929 SCV000839991 pathogenic Familial hypercholesterolemia 1 2017-05-25 criteria provided, single submitter clinical testing The c.680_681del (p.Asp227Glyfs*12) variant in the LDLR gene has been detected in multiple patients with hypercholesterolemia [PMID 8093663, 14974088, 10559517]. This 2 bp deletion in exon 4 results in a frameshift and the creation of a premature stop codon. This variant is thus predicted to result in a loss of function of the protein. This variant is rare and has not been detected in the ExAC database. This variant thus classified as pathogenic.
OMIM RCV000003929 SCV000024094 pathogenic Familial hypercholesterolemia 1 1993-01-01 no assertion criteria provided literature only
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000003929 SCV000268579 pathogenic Familial hypercholesterolemia 1 2008-06-09 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000003929 SCV000606195 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000517763 SCV000925127 pathogenic not provided 2017-12-15 no assertion criteria provided provider interpretation p.Asp227Glyfs*12 (c.680_681delAC) in exon 4 of the LDLR gene (NM_000527.4; chr19-11216262-AC-) This variant is also known as 79-680delAC and p.D206fs in the literature. SCICD Classification: pathogenic variant based on mechanism of disease, strong case data and rarity in the general population. We do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: LDLR: LDL receptors are located on the surface of the liver and play an important role in LDL recycling. Pathogenic variants in LDLR account for 80% of cases of familial hypercholesterolemia. Both missense and truncating/frameshift variants can be pathogenic. Case data (not including our patient): at least 6 patients with FH. ClinVar: Classified as pathogenic or likely pathogenic by 5 labs: LDLR-LOVD, British Heart Foundation, Robarts Research Institute,University of Western Ontario, Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, m voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum, CardiovasLaboratoriucular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital. Cases in the literature: Gudnason et al., 1993: 3 out of 200 patients with FH (2 of British origin, 1 Afrikaaner) Dedoussis et al., 2004: 1 out of 200 patients with FH (ancestry unclear - 100 German and 100 Greek patients). Wang et al., 2016: 1 out of 313 patients with FH. Bunn et al., 2002: A very similar deletion (c.679-680delAC) was present in 1 out of 150 patients with FH. Segregation data: none reported Functional data: none reported for this specific variant; however, truncating variants in LDLR are a known mechanism of disease. Conservation data: The asparagine at codon 227 is complete conserved across species. Neighboring amino acids are also completely conserved. Population data: Highest MAF in European population: 0.0009%. The variant was reported online in 1 of 122,394 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 1 of 55,342 individuals of European descent (MAF=0.0009). 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. 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).

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