Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000237741 | SCV004022382 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2023-03-20 | reviewed by expert panel | curation | The NM_000527.5 (LDLR):c.2473A>G (p.Asn825Asp) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4_Supporting, PM5) 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: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL = 0.93. PP4: Variant meets PM2 and is identified in >1 index cases who fulfil FH diagnostic criteria after alternative causes of high cholesterol were excluded. PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated index cases who fulfil FH diagnostic criteria. One index case fulfil criteria of TC > 8mmol/l and strong family history of CAD, Laurie et al, 2004, Canterbury Health Laboratories, New Zealand, PMID: 15556094. One index case with DLCN score >=6, Meshkov et al, 2021, National Medical Research Center for Therapy and Preventive Medicine, Russia, PMID: 33418990. PM5: Two other missense variants in the same codon: NM_000527.5 (LDLR):c.2475C>G (p.Asn825Lys), (ClinVarID 161265), is classified as Likely Pathogenic; NM_000527.5 (LDLR):c.2475C>A (p.Asn825Lys), (ClinVarID 252341), is classified as Pathogenic by these guidelines, therefore PM5 is met. |
| LDLR- |
RCV000237741 | SCV000296014 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| All of Us Research Program, |
RCV000237741 | SCV004824286 | uncertain significance | Hypercholesterolemia, familial, 1 | 2023-06-08 | criteria provided, single submitter | clinical testing | This missense variant (also known as p.Asn804Asp in the mature protein) replaces asparagine with aspartic acid at codon 825 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). To our knowledge, functional studies have not been reported for this variant. This LDLR variant has been reported in one heterozygous individual affected with familial hypercholesterolemia (PMID: 33418990). This variant has also been observed in compound heterozygous state with a different LDLR variant of uncertain significance in an individual affected with severe homozygous familial hypercholesterolemia (PMID: 15556094). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Asn825Lys, is considered to be disease-causing (ClinVar variation ID: 161265), suggesting that asparagine at this position is important for LDLR protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |