Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000237696 | SCV002506398 | uncertain significance | Hypercholesterolemia, familial, 1 | 2022-02-10 | reviewed by expert panel | curation | The NM_000527.5 (LDLR): c.895G>A (p.Ala299Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS4_Supporting, PS3_Supporting) 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 Met: PopMAX MAF = 0.00005 in East Asian population in gnomAD (gnomAD v2.1.1). PP4 Met: This variant meets PM2 and is identified in > 1 index cases who met clinical criteria for FH after alternative causes for high cholesterol were excluded. PS4_Supporting Met: Variant meets PM2 and is identified in 2 unrelated index cases who fulfil DLCN criteria for FH (1 case from Unidad de Biof´ısica , Centro Mixto CSIC-UPV/EHU and Departamento de Bioqu´ımica, Universidad del Pa´ıs Vasco, Bilbao, Spain, PMID 21990180; 1 case from Lipid Clinic, Fundación Jiménez Díaz, Madrid, Spain, PMID 19318025). PS3_Supporting Met: Heterozygous patient lymphocytes FACS assays (level 3 functional assay) showed normal cell surface localization, but 50% LDL-LDLR uptake and binding (Etxebarria et al, Unidad de Biof´ısica, Centro Mixto CSIC-UPV/EHU and Departamento de Bioqu´ımica, Universidad del Pa´ıs Vasco, Bilbao, Spain, PMID 21990180). PP3 not met: REVEL score = 0.543, which is below the threshold of 0.75. This variant does not creating de novo acceptor or donor site and is not predicted to alter splicing. PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.895G>T (p.Ala299Ser) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met. |
| LDLR- |
RCV000237696 | SCV000295034 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Fundacion Hipercolesterolemia Familiar | RCV000237696 | SCV000607516 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
| Labcorp Genetics |
RCV001854894 | SCV002183284 | uncertain significance | Familial hypercholesterolemia | 2021-05-30 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this variant affects LDLR protein function (PMID: 21990180). This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 21990180, 19318025). ClinVar contains an entry for this variant (Variation ID: 251507). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 299 of the LDLR protein (p.Ala299Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. |