Submissions for variant NM_000527.5(LDLR):c.1066G>A (p.Asp356Asn)

gnomAD frequency: 0.00002  dbSNP: rs767767730

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238202	SCV000295195	likely benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
GeneDx	RCV000522393	SCV000617507	uncertain significance	not provided	2024-04-15	criteria provided, single submitter	clinical testing	Reported in individuals with hypercholesterolemia (PMID: 15998910, 32977124, 20145306); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(D335N); This variant is associated with the following publications: (PMID: 18325082, 19837725, 20145306, 32977124, 15998910)
Color Diagnostics, LLC DBA Color Health	RCV001182457	SCV001347899	uncertain significance	Familial hypercholesterolemia	2023-02-09	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Asp335Asn in the mature protein) replaces aspartic acid with asparagine at codon 356 of the LDLR protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15998910, 20145306). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 32977124). This variant has been identified in 3/251248 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Three, rare missense variants occurring at the same codon (p.Asp356His, p.Asp356Tyr, p.Asp356Ala) have been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 9104431, 11851376, 15256764, 19319977, 20145306, 20809525, 35929461), indicating that aspartic acid at this position is important for LDLR protein function. 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.
Ambry Genetics	RCV002411083	SCV002717374	uncertain significance	Cardiovascular phenotype	2024-09-18	criteria provided, single submitter	clinical testing	The p.D356N variant (also known as c.1066G>A), located in coding exon 8 of the LDLR gene, results from a G to A substitution at nucleotide position 1066. The aspartic acid at codon 356 is replaced by asparagine, an amino acid with highly similar properties. This alteration (also referred to as p.D335N) has been reported as heterozygous and compound heterozygous in subjects with familial hypercholesterolemia (FH) (Alharbi KK et al. Genome Res, 2005 Jul;15:967-77; Chmara M et al. J Appl Genet, 2010;51:95-106; Bertolini S et al. Atherosclerosis, 2020 11;312:72-78; Doi T et al. J Am Heart Assoc, 2021 02;10:e018263; Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001182457	SCV003455720	uncertain significance	Familial hypercholesterolemia	2025-01-21	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 356 of the LDLR protein (p.Asp356Asn). This variant is present in population databases (rs767767730, gnomAD 0.006%). This missense change has been observed in individuals with familial hypercholesterolemia and/or homozygous familial hypercholesterolemia (PMID: 15998910, 19843101, 32977124). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be benign with a negative predictive value of at least 95%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. This variant is also known as p.Asp335Asn. ClinVar contains an entry for this variant (Variation ID: 251643). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt LDLR protein function with a negative predictive value of 95%. This variant disrupts the p.Asp356 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9104431, 33740630). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387819	SCV004099697	uncertain significance	not specified	2023-09-11	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1066G>A (p.Asp356Asn) results in a conservative amino acid change located in the EGF-like calcium-binding domain (IPR001881) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251248 control chromosomes (e.g., 3 heterozygotes; gnomAD v2.1 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1066G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia (e.g. Alharbi_2005, Leigh_2008, Taylor_2009, Chmara_2010, Bertolini_2020), however without strong evidence for causality (e.g., co-segregation data). These reports therefore do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15998910, 32977124, 20145306, 18325082, 19843101). Six submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments of pathogenicity (uncertain significance, n = 5; likely benign, n = 1). Additionally, other missense variants affecting the same codon, including p.Asp356Val and p.Asp356Tyr, have been reported in multiple patients with familial hypercholesterolemia (PMIDs: 30745730, 34011801, 34037665, 35480308, 9104431, 33740630) and are classified as pathogenic/likely pathogenic in ClinVar, suggesting that disruption of this residue is clinically significant. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
All of Us Research Program, National Institutes of Health	RCV000238202	SCV004820262	uncertain significance	Hypercholesterolemia, familial, 1	2024-07-02	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Asp335Asn in the mature protein) replaces aspartic acid with asparagine at codon 356 of the LDLR protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15998910, 20145306). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 32977124). This variant has been identified in 3/251248 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Three, rare missense variants occurring at the same codon (p.Asp356His, p.Asp356Tyr, p.Asp356Ala) have been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 9104431, 11851376, 15256764, 19319977, 20145306, 20809525, 35929461), indicating that aspartic acid at this position is important for LDLR protein function. 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.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238202	SCV000606315	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV001182457	SCV001460268	uncertain significance	Familial hypercholesterolemia	2020-09-16	no assertion criteria provided	clinical testing