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

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV002518489	SCV000295665	uncertain significance	Familial hypercholesterolemia	2016-03-25	criteria provided, single submitter	literature only	NM_000527.5(LDLR):c.1801G>C (p.Asp601His) has been reported in South America (PMID: 11933210; 25461735), with a definitive FH case in PMID: 33231818, allowing ACMG criteria PP4 to be scored. PM2 can also be scored, however, PP3 can not be scored as the REVEL score of 0.605 is below the threshold of >0.75 for a pathogenic prediction. The overall classification for this variant is Uncertain significance.
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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002518489	SCV003520106	pathogenic	Familial hypercholesterolemia	2023-02-27	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 252038). For these reasons, this variant has been classified as Pathogenic. 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. 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 missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11933210, 25461735, 33231818). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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).