ClinVar Miner

Submissions for variant NM_000384.3(APOB):c.7285T>A (p.Ser2429Thr) (rs72653092)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000203158 SCV000257685 uncertain significance Familial hypercholesterolemia 2015-03-06 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224080 SCV000281157 uncertain significance not provided 2016-04-18 criteria provided, single submitter clinical testing Converted during submission to Uncertain significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000456013 SCV000538324 uncertain significance not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Few reports, no segs, ExAC: 0.1% (92/66598) European chromosomes
Invitae RCV000473569 SCV000554822 likely benign Hypercholesterolemia, autosomal dominant, type B; Hypobetalipoproteinemia, familial, 1 2017-11-19 criteria provided, single submitter clinical testing
GeneDx RCV000456013 SCV000582163 uncertain significance not specified 2017-05-12 criteria provided, single submitter clinical testing The S2429T variant of uncertain significance in the APOB gene has been reported previously in at least one individual with hypertriglyceridemia and possible FH (Johansen et al., 2010; Radovica-Spalvine et al., 2015). Nevertheless, this variant has also been reported in another family with FH, where three family members who were heterozygous for the S2429T variant in the APOB gene in addition to at least one pathogenic variant in the LDLR gene had lower LDL-C levels than family members who did not harbor the S2429T variant (Rabacchi et al., 2016). The index cases in this family, identical twins who were compound heterozygous for two different LDLR pathogenic variants and who lacked the S2429T variant in the APOB gene, had LDL-C levels ranging from 9.13-11.89 mmol/L (Rabacchi et al., 2016). Two siblings who were also compound heterozygous for the familial LDLR pathogenic variants and who did harbor the S2429T variant in the APOB gene, had LDL-C levels ranging from 7.13-8.27 mmol/L. The mother of these individuals, who harbored a pathogenic LDLR variant and the S2429T variant in the APOB gene, had LDL-C levels in the normal range, leading the authors to hypothesize that the S2429T variant may have an LDL-lowering effect (Rabacchi et al., 2016). The S2429T variant has been classified as a variant of uncertain significance by three other clinical laboratories and as a likely benign variant by one other clinical laboratory in ClinVar (SCV000257685.2, SCV000281157.1, SCV000538324.1, SCV000554822.1; Landrum et al., 2016). This variant is observed in 0.1-0.2% of alleles from individuals of European ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S2429T variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position not conserved. Furthermore, in silico analysis predicts this variant likely does not alter the protein structure/function.
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000203158 SCV000588443 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Genetic Services Laboratory, University of Chicago RCV000456013 SCV000593266 uncertain significance not specified 2016-10-20 criteria provided, single submitter clinical testing
Color RCV000203158 SCV000687259 uncertain significance Familial hypercholesterolemia 2017-09-25 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the alpha 2 domain of the APOB protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in a Latvian individual with suspected hypercholesterolemia (PMID 26415676). In an Italian family with hypercholesterolemia caused by biallelic LDLR mutations, this variant was suggested to have LDL-C lowering effect (PMID 27578127). This variant has been identified in 92/66598 non-Finnish European chromosomes by the Exome Aggregation Consortium (ExAC) general population database.
Color RCV000771126 SCV000902877 likely benign Familial hypercholesterolemias 2018-03-26 criteria provided, single submitter clinical testing Likely Benign based on current evidence: This missense variant (also known as p.Ser2402Thr in the mature protein) is located in the alpha 2 domain of the APOB protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in a Latvian individual with suspected hypercholesterolemia (PMID: 26415676). In an Italian family with hypercholesterolemia caused by biallelic LDLR mutations, this variant was suggested to have LDL-C lowering effect (PMID: 27578127). This variant has been identified in 136/126166 non-Finnish European chromosomes (0.11%) and 39/10136 Ashkenazi Jewish chromosomes (0.38%) in the general population by the Genome Aggregation Database (gnomAD). This variant allele frequency is greater than expected for the disorder based on prevalence, penetrance, and genetic heterogeneity. Based on available evidence, this variant is classified as Likely Benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000224080 SCV000987694 uncertain significance not provided criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000417323 SCV000503553 uncertain significance Hypercholesterolemia 2016-08-01 no assertion criteria provided research Found in patient having exome sequencing for an unrelated indication. No known history hypercholesterolemia.

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