ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1801G>C (p.Asp601His)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237978 SCV000295665 likely benign Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000237978 SCV000588608 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Iberoamerican FH Network RCV000237978 SCV000748154 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Mendelics RCV000237978 SCV002516656 pathogenic Hypercholesterolemia, familial, 1 2022-05-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV002411091 SCV002717317 uncertain significance Cardiovascular phenotype 2017-10-23 criteria provided, single submitter clinical testing The p.D601H variant (also known as c.1801G>C), located in coding exon 12 of the LDLR gene, results from a G to C substitution at nucleotide position 1801. The aspartic acid at codon 601 is replaced by histidine, an amino acid with similar properties, and is located in the LDL-receptor class B repeat 5. This alteration (with legacy nomenclature p.D680H) has been reported in 2 Brazilian familial hypercholesterolemia cohorts; however, clinical details were limited (Salazar LA et al. Hum. Mutat. 2002;19:462-3; Jannes CE et al. Atherosclerosis. 2015;238:101-7). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV002518489 SCV003520106 pathogenic Familial hypercholesterolemia 2023-02-27 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 601 of the LDLR protein (p.Asp601His). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11933210, 25461735, 33231818). ClinVar contains an entry for this variant (Variation ID: 252038). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LDLR protein function. This variant disrupts the p.Asp601 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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