ClinVar Miner

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

gnomAD frequency: 0.00002  dbSNP: rs767767730
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Total submissions: 9
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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 2021-10-13 criteria provided, single submitter clinical testing Reported in individuals with hypercholesterolemia (Alharbi et al., 2005; Bertolini et al., 2020; Chmara et al., 2010), though the authors of one paper describe p.(D356N) as a "non-pathogenic variant" (Chmara et al., 2010); 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; 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 2022-06-08 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 has been reported as heterozygous and compund 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). This amino acid position is well 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.
Invitae RCV001182457 SCV003455720 uncertain significance Familial hypercholesterolemia 2021-09-17 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 356 of the LDLR protein (p.Asp356Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs767767730, ExAC 0.006%). This variant has been observed in individual(s) with hypercholesterolemia (PMID: 15998910). This variant is also known as p.Asp335Asn. ClinVar contains an entry for this variant (Variation ID: 251643). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant disrupts the p.Asp356 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 9104431, 30745730), which suggests that this may be a clinically significant amino acid residue. 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 2023-11-20 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

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