Submissions for variant NM_000527.5(LDLR):c.514G>C (p.Asp172His)

dbSNP: rs879254554

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237481	SCV000294757	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV003581601	SCV004298321	pathogenic	Familial hypercholesterolemia	2024-01-04	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 172 of the LDLR protein (p.Asp172His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 10882754, 33732287). This variant is also known as D151H. ClinVar contains an entry for this variant (Variation ID: 251267). 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 expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Asp172 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10532689, 16806138, 25545329). 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.
Rajaie Cardiovascular, Medical and Research Center, Iran University of Medical Sciences	RCV000237481	SCV001467721	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research