Submissions for variant NM_000527.5(LDLR):c.2119G>A (p.Asp707Asn)

gnomAD frequency: 0.00001  dbSNP: rs879255142

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238203	SCV000295880	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Ambry Genetics	RCV002418072	SCV002726431	uncertain significance	Cardiovascular phenotype	2022-07-07	criteria provided, single submitter	clinical testing	The p.D707N variant (also known as c.2119G>A), located in coding exon 14 of the LDLR gene, results from a G to A substitution at nucleotide position 2119. The aspartic acid at codon 707 is replaced by asparagine, an amino acid with highly similar properties. This variant was reportedly detected in association with FH; however, clinical details were not provided (Usifo E et al. Ann Hum Genet, 2012 Sep;76:387-401). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003581643	SCV004284878	uncertain significance	Familial hypercholesterolemia	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 707 of the LDLR protein (p.Asp707Asn). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 22881376). ClinVar contains an entry for this variant (Variation ID: 252225). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV003581643	SCV004359058	uncertain significance	Familial hypercholesterolemia	2023-04-05	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Asp686Asn in the mature protein) replaces aspartic acid with asparagine at codon 707 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 22881376). This variant has been identified in 1/250770 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV000238203	SCV004818500	uncertain significance	Hypercholesterolemia, familial, 1	2024-04-16	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Asp686Asn in the mature protein) replaces aspartic acid with asparagine at codon 707 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 22881376). This variant has been identified in 1/250770 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017565	SCV004847719	uncertain significance	not provided	2021-11-16	criteria provided, single submitter	clinical testing	The p.Asp707Asn variant in LDLR has been reported in at least one individual with familial hypercholesterolemia (Usifo 2012 PMID:22881376). It has also been identified in 0.001% (1/113608) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3.
Mayo Clinic Laboratories, Mayo Clinic	RCV004017565	SCV005413323	likely pathogenic	not provided	2023-12-27	criteria provided, single submitter	clinical testing	PP3, PP4, PM2_moderate, PM5