Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000238200 | SCV002506396 | uncertain significance | Hypercholesterolemia, familial, 1 | 2022-02-10 | reviewed by expert panel | curation | The NM_000527.5 (LDLR): c.895G>T (p.Ala299Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4) 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: This variant is absent in gnomAD (gnomAD v2.1.1). PP4 Met: This variant meets PM2 and is identified in 1 index case who met clinical criteria for FH after alternative causes for high cholesterol were excluded (Lipid Clinic, Fundación Jiménez Díaz, Madrid, Spain, PMID 19318025). PP3 not Met: REVEL score = 0.519, which is below the threshold of 0.75. Functional data on splicing is not available, in silico splicing prediction is required. Variant is exonic and at least 50bp downstream from acceptor site and creates GT. MES scores: de novo donor = -2.99, authentic donor = 8.14. De novo score is negative and not used, therefore the variant is not predicted to alter splicing. BP4 not applicable: REVEL score is > 0.5, therefore BP4 is not applicable. PS3 not met: Functional data is not available. PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.895G>A (p.Ala299Thr) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met. |
| LDLR- |
RCV000238200 | SCV000295035 | likely benign | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Fundacion Hipercolesterolemia Familiar | RCV000238200 | SCV000607517 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
| Labcorp Genetics |
RCV003581609 | SCV004298336 | likely pathogenic | Familial hypercholesterolemia | 2023-08-16 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 299 of the LDLR protein (p.Ala299Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 18096825, 19318025). ClinVar contains an entry for this variant (Variation ID: 251508). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LDLR protein function. This variant disrupts the p.Ala299 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 21990180), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Ambry Genetics | RCV004020953 | SCV004897975 | uncertain significance | Cardiovascular phenotype | 2023-12-18 | criteria provided, single submitter | clinical testing | The c.895G>T (p.A299S) alteration is located in exon 6 (coding exon 6) of the LDLR gene. This alteration results from a G to T substitution at nucleotide position 895, causing the alanine (A) at amino acid position 299 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |