ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1951G>A (p.Asp651Asn) (rs730882110)

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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 RCV000238255 SCV000295769 uncertain significance Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000238255 SCV000503436 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 , family members = 3 with co-segregation / previously described in association with FH/Software predictions: Conflicting
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000238255 SCV000540849 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing
Fundacion Hipercolesterolemia Familiar RCV000238255 SCV000607657 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590648 SCV000697217 likely pathogenic Familial hypercholesterolemia 2016-05-19 criteria provided, single submitter clinical testing Variant summary: The LDLR c.1951G>A (p.Asp651Asn) variant involves the alteration of a conserved nucleotide and is located in 'precursor homology' domain. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant was found in 1/131578 control chromosomes at a frequency of 0.0000076, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). This variant has been found in three apparently non-related FH patients (Mozas_2004) as well as in one patient with myocardial infarction (Do_2015). Other missense changes at this codon such as Asp651Tyr has also been detected in FH patients, suggesting that the codon may be a mutational hot-spot. Taken together, it variant has been classified as a Probable Disease Variant (or likely pathogenic).
CeGaT Praxis fuer Humangenetik Tuebingen RCV000162005 SCV001151670 uncertain significance not provided 2018-05-01 criteria provided, single submitter clinical testing
Invitae RCV000590648 SCV001221619 uncertain significance Familial hypercholesterolemia 2020-01-15 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 651 of the LDLR protein (p.Asp651Asn). 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 (rs730882110, ExAC 0.001%). This variant has been observed in individual(s) with LDLR-related conditions (PMID: 15241806, 25487149, Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as p.D630N in the literature. ClinVar contains an entry for this variant (Variation ID: 183128). This variant has been reported to have conflicting or insufficient data to determine the effect on LDLR protein function (PMID: 25647241). This variant disrupts the p.Asp651 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 16389549, 19318025), 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.
Color Health, Inc RCV000590648 SCV001352604 uncertain significance Familial hypercholesterolemia 2020-01-15 criteria provided, single submitter clinical testing
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000162005 SCV000189580 not provided not provided no assertion provided in vitro

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