ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1474G>C (p.Asp492His) (rs373646964)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000587515 SCV000909509 likely pathogenic Familial hypercholesterolemias 2018-07-09 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant (also known as p.Asp471His in the mature protein) is located in the LDLR type B repeat 3 of the EGF precursor homology domain of the LDLR protein. This variant changes a highly conserved Asp residue within the functionally important YWTD motif. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia in UK (PMID: 10208479, 15556093, 16389549). This variant is rare in the general population and has been identified in 2/277190 chromosomes by the Genome Aggregation Database (gnomAD). Different missense variants at the same position (p.Asp492Asn and p.Asp492Gly) are considered to be disease-causing. Based on available evidence, this variant is classified as Likely Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000587515 SCV000697198 likely pathogenic Familial hypercholesterolemias 2017-05-18 criteria provided, single submitter clinical testing Variant summary: The LDLR c.1474G>C (p.Asp492His) variant involves the alteration of a highly conserved nucleotide. The variant is located within the low-density lipoprotein receptor repeat class B. This domain is also known as the YWTD motif after the most conserved region of the repeat. 5/5 in silico tools predict a damaging outcome for this variant however, no experimental data confirming impact of the variant on the protein function have been reported at the time of evaluation. The variant is absent from the large control population dataset of ExAC (0/121280 chrs tested) but is identified in the larger dataset of gnomAD at a frequency of 0.00000721 (2/277190), which does not exceed the maximal expected frequency of a pathogenic allele (0.0012) in this gene. The variant has been identified in at least 1 affected individual with severely elevated cholesterol level (Heath, 1999). The codon Asp492 appears to be a mutational hot-spot as other alterations c.1474G>A (p.Asp492Asn), c.1475A>G (p.Asp492Gly) have been reported in multiple patients with established dx of FH. In addition, a clinical diagnostic laboratory/reputable database classified this variant as Likely Pathogenic. Taken together, following ACMG recommendations, this variant is classified as Likely Pathogenic.
Invitae RCV000238035 SCV000830403 uncertain significance Familial hypercholesterolemia 2018-05-14 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 492 of the LDLR protein (p.Asp492His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with familial hypercholesterolemia (PMID: 10208479). This variant is also described as p.Asp471His (D471H) in the literature. ClinVar contains an entry for this variant (Variation ID: 251864). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). The p.Asp492 amino acid residue in LDLR has been determined to be clinically significant (PMID: 10230472, 23375686, 25487149, 25936317, 9763532). This suggests that variants that disrupt this residue are likely to be causative of disease. 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.
LDLR-LOVD, British Heart Foundation RCV000238035 SCV000295459 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000238035 SCV000606439 pathogenic Familial hypercholesterolemia no assertion criteria provided research

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