Total submissions: 15
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000844748 | SCV000271387 | pathogenic | Homozygous familial hypercholesterolemia | 2015-12-21 | criteria provided, single submitter | clinical testing | The p.Trp87Gly variant in LDLR is a well-established pathogenic variant for fami lial hypercholesterolemia (Leitersdorf 1990, Jensen 1996, Vohl 1997, Tybjaerg-Ha nsen 2005, Futema 2013), and is a known founder mutation in the French Canadian population where it has been reported in >400 individuals with FH, including >15 homozygous individuals (Vohl 1997). It has also been identified in 7/126722Euro pean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broad institute.org; dbSNP rs121908025); however, this frequency is low enough to be c onsistent with the frequency of FH in the general population. Additionally, in v itro functional studies provide some evidence that the p.Trp87Gly variant may im pact protein function (Leitersdorf 1990). In summary, this variant meets our cri teria to be classified as pathogenic for FH in an autosomal dominant manner base d upon its identification in a large number of affected individuals and low freq uency in controls. ACMG/AMP Criteria applied: PS4; PM3; PM2_Supporting; PP3; PS3 _Supporting. |
Invitae | RCV000776466 | SCV000285027 | pathogenic | Familial hypercholesterolemia | 2019-08-05 | criteria provided, single submitter | clinical testing | This sequence change replaces tryptophan with glycine at codon 87 of the LDLR protein (p.Trp87Gly). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and glycine. This variant is clearly defined as a familial hypercholesterolemia causative allele (PMID: 2318961, 12553167, 16542394). It is a founder mutation in the Dutch population, and is common in individuals of European ancestry. This variant is also known as p.W66G in the literature. ClinVar contains an entry for this variant (Variation ID: 3685). Experimental studies have shown that this missense change leads to an LDL receptor protein that is unable to properly bind LDL (PMID: 8098448). For these reasons, this variant has been classified as Pathogenic. |
LDLR- |
RCV000003870 | SCV000294560 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Robarts Research Institute, |
RCV000003870 | SCV000484716 | likely pathogenic | Familial hypercholesterolemia 1 | criteria provided, single submitter | clinical testing | ||
Centre de Génétique Moléculaire et Chromosomique, |
RCV000003870 | SCV000503120 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subjects mutated among 2600 FH index cases screened = 9 , family members = 7 with co-segregation / frequently associated with c.1975A>C, p.Thr659Pro (2 index cases), Subnormal LDLR activity / Software predictions: Damaging |
Molecular Genetics Laboratory, |
RCV000003870 | SCV000540721 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-11-05 | criteria provided, single submitter | clinical testing | |
U4M - |
RCV000003870 | SCV000583644 | pathogenic | Familial hypercholesterolemia 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | |
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV000622852 | SCV000740415 | likely pathogenic | not provided | 2017-07-11 | criteria provided, single submitter | clinical testing | |
Color | RCV000776466 | SCV000912015 | pathogenic | Familial hypercholesterolemia | 2018-01-29 | criteria provided, single submitter | clinical testing | Pathogenic variant based on current evidence: This missense variant (also known as p.Trp66Gly in the mature protein) is located in the second LDLR type A repeat of the ligand binding domain of the LDLR protein. 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. Experimental studies have demonstrated that the variant protein showed reduced LDL binding (PMID: 8645371, 10735631). This variant has been identified in over 500 individuals affected with familial hypercholesterolemia (PMID: 8098448, 9272705, 12553167, 16542394, 2318961). This variant is common in individuals of European descent and is considered a founder mutation in the French-Canadian population (PMID: 9272705). Homozygous individuals have shown much higher LDL-C levels than heterozygous individuals (PMID: 8098448). This variant has been identified in 8/277232 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic. |
Institute of Human Genetics, |
RCV000003870 | SCV001428736 | likely pathogenic | Familial hypercholesterolemia 1 | 2020-02-03 | criteria provided, single submitter | clinical testing | |
Brunham Lab, |
RCV000003870 | SCV001432641 | pathogenic | Familial hypercholesterolemia 1 | 2019-03-13 | criteria provided, single submitter | research | |
Human Genome Sequencing Center Clinical Lab, |
RCV000776466 | SCV001435004 | pathogenic | Familial hypercholesterolemia | 2020-02-04 | criteria provided, single submitter | clinical testing | The c.259T>G (p.Trp87Gly) variant in the LDLR gene has been reported in multiple individuals with familial hypercholesterolemia (PMID: 2318961, 8054972, 8645371, 9259195, 9104431). It is located in the functionally important second LDLR type A repeat. Functional studies have demonstrated a deleterious effect of the p.Trp87Gly variant on LDL binding (PMID: 2318961, 8645371, 10735631). The variant is observed in gnomAD at a low minor allele frequency (8/282882). Multiple algorithms predicted this change to be deleterious. Therefore, the c.259T>G (p.Trp87Gly) variant in the LDLR gene is classified as pathogenic. |
OMIM | RCV000003870 | SCV000024035 | pathogenic | Familial hypercholesterolemia 1 | 1994-04-01 | no assertion criteria provided | literature only | |
Cardiovascular Genetics Laboratory, |
RCV000003870 | SCV000268547 | pathogenic | Familial hypercholesterolemia 1 | 2008-12-18 | no assertion criteria provided | clinical testing | |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000003870 | SCV000606051 | pathogenic | Familial hypercholesterolemia 1 | no assertion criteria provided | research |