ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.661G>T (p.Asp221Tyr) (rs875989906)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237890 SCV000294861 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter research
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237890 SCV000322907 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research 0/190 non-FH alleles; 0/50 normolipidemic individuals
Fundacion Hipercolesterolemia Familiar RCV000237890 SCV000607480 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Invitae RCV001050137 SCV001214231 pathogenic Familial hypercholesterolemia 2019-03-07 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 221 of the LDLR protein (p.Asp221Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with familial hypercholesterolemia in a family (PMID: 9237502) and has been observed in individuals affected with this condition (PMID: 7649546, 7573037, 23375686, 10206683, 17765246, Invitae). This variant is also known as D200Y in the literature. ClinVar contains an entry for this variant (Variation ID: 251356). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Asp221 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15523646,23375686, 11196104, 15241806, 220236128, 2698793, 25461735). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV000237890 SCV001428968 pathogenic Familial hypercholesterolemia 1 2017-08-23 criteria provided, single submitter clinical testing

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