ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.898A>G (p.Arg300Gly)

gnomAD frequency: 0.00001  dbSNP: rs767618089
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000237850 SCV002817154 likely pathogenic Hypercholesterolemia, familial, 1 2022-10-28 reviewed by expert panel curation The NM_000527.5(LDLR):c.898A>G (p.Arg300Gly) variant is classified as likely Pathogenic variant for Familial Hypercholesterolemia by applying evidence code PM2, PS3 and PS4 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 = 0.00003 in European (Non-Finnish) exomes (gnomAD v2.1.1) PS3_Met : Level 1 assay: Study of the whole LDLR cycle in Heterologous cells (CHO-ldlA7 cells), WB+FACS+CLSM. LDLR expression was not statistically different as compared to control. Conversely, LDL binding (<60%) and uptake (<60%) were significantly decreased (P<0.001). Interestingly, although the variant affects LDL binding and uptake, do not affect VLDL uptake. This reveals that the conformational change occurring in the module does not propagate to the whole ligand binding domain. (from PMID:25545329)
LDLR-LOVD, British Heart Foundation RCV000237850 SCV000295037 uncertain significance Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237850 SCV000583755 pathogenic Hypercholesterolemia, familial, 1 2017-03-30 criteria provided, single submitter clinical testing
Fundacion Hipercolesterolemia Familiar RCV000237850 SCV000607518 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000237850 SCV002499073 pathogenic Hypercholesterolemia, familial, 1 2022-02-21 criteria provided, single submitter clinical testing PS3, PS4_Moderate, PM1, PM2
3billion RCV000237850 SCV002572850 pathogenic Hypercholesterolemia, familial, 1 2022-09-01 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 25545329). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.56; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with LDLR -related disorder (ClinVar ID: VCV000251510 / PMID: 19318025). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 25545329 , 28965616 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
CeGaT Center for Human Genetics Tuebingen RCV003456385 SCV004185155 likely pathogenic not provided 2023-11-01 criteria provided, single submitter clinical testing LDLR: PM1, PM2, PS4:Moderate, PS3:Supporting

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