ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.440C>T (p.Thr147Ile)

dbSNP: rs879254524
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000237461 SCV004022432 likely pathogenic Hypercholesterolemia, familial, 1 2023-04-28 reviewed by expert panel curation The NM_000527.5(LDLR):c.440C>T (p.Thr147Ile) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3_Supporting, PM1, PM2, and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS3_Supporting: Level 3 assays: PMID 21865347: Htz Patient lymphocytes, FACS assays - results - 55-70% LDLR activity ---- results are below 85% of wild-type activity. So PS3_Supporting is met. PM1: Variant meets PM2 and is on exon 4. So PM1 is met. PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So PM2 is met. PP3: REVEL = 0.811. It is above 0.75, so PP3 is met.
LDLR-LOVD, British Heart Foundation RCV000237461 SCV000294710 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237461 SCV000599332 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter curation
Color Diagnostics, LLC DBA Color Health RCV001186868 SCV001353458 likely pathogenic Familial hypercholesterolemia 2023-02-16 criteria provided, single submitter clinical testing This missense variant (also known as p.Thr126Ile in the mature protein) replaces threonine with isoleucine at codon 147 in the LDLR type A repeat 4 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in a partial loss of LDLR function (PMID: 21865347). Threonine at this position is located in a functionally important region, and missense variants at this position are expected to interrupt glycosylation of linker regions in LDLR (PMID: 24798328). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 21865347, 34297352; Color internal data; communication with an external laboratory; ClinVar SCV002633357.1). 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 Likely Pathogenic.
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II RCV000237461 SCV001653593 pathogenic Hypercholesterolemia, familial, 1 2021-05-24 criteria provided, single submitter clinical testing Reduced activity in functional assays.
AiLife Diagnostics, AiLife Diagnostics RCV002223826 SCV002502824 likely pathogenic not provided 2021-12-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV002327173 SCV002633357 likely pathogenic Cardiovascular phenotype 2021-09-13 criteria provided, single submitter clinical testing The p.T147I variant (also known as c.440C>T), located in coding exon 4 of the LDLR gene, results from a C to T substitution at nucleotide position 440. The threonine at codon 147 is replaced by isoleucine, an amino acid with similar properties. This alteration was reported in two individuals from a familial hypercholesterolemia cohort and shown to reduce LDLR activity to 56% of normal levels in vivo (Romano M et al. J. Lipid Res., 2011 Nov;52:2095-100). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000237461 SCV003932171 likely pathogenic Hypercholesterolemia, familial, 1 2023-03-06 criteria provided, single submitter clinical testing PS3, PM2, PS4_Moderate, PP3

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