Total submissions: 19
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Institute for Integrative and Experimental Genomics, |
RCV000003882 | SCV000212137 | likely pathogenic | Familial hypercholesterolemia 1 | criteria provided, single submitter | research | ||
LDLR- |
RCV000003882 | SCV000295341 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Robarts Research Institute, |
RCV000003882 | SCV000484726 | likely pathogenic | Familial hypercholesterolemia 1 | criteria provided, single submitter | clinical testing | ||
Centre de Génétique Moléculaire et Chromosomique, |
RCV000003882 | SCV000503327 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subjects mutated among 2600 FH index cases screened = 12 , family members = 6 with co-segregation / FH-Afrikaner-2, < 2% LDLR Activity / Software predictions: Conflicting |
Molecular Genetics Laboratory, |
RCV000003882 | SCV000540808 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-11-05 | criteria provided, single submitter | clinical testing | |
U4M - |
RCV000003882 | SCV000583816 | pathogenic | Familial hypercholesterolemia 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | |
Laboratory of Genetics and Molecular Cardiology, |
RCV000003882 | SCV000588571 | pathogenic | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | research | |
Fundacion Hipercolesterolemia Familiar | RCV000003882 | SCV000607578 | pathogenic | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | research | |
Invitae | RCV000775062 | SCV000627017 | pathogenic | Familial hypercholesterolemia | 2019-12-18 | criteria provided, single submitter | clinical testing | This sequence change replaces valine with methionine at codon 429 of the LDLR protein (p.Val429Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs28942078, ExAC 0.006%). This variant has been reported in the literature in the homozygous state segregating with disease in a single family (PMID: 21925660) and in several individuals both in the homozygous and heterozygous state affected with familial hypercholesterolemia (PMID: 11668627, 23375686, 2569482, 11196104, 19837725, 15256764, 11139254, 21475731). This variant is also known as p.Val408Met in the literature. ClinVar contains an entry for this variant (Variation ID: 3694). Experimental studies have shown that this missense change causes slower processing of precursor LDLR protein to the mature protein and faster degradation of the protein (PMID: 2569482). For these reasons, this variant has been classified as Pathogenic. |
Iberoamerican FH Network | RCV000003882 | SCV000748052 | pathogenic | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | research | |
Fulgent Genetics, |
RCV000003882 | SCV000894174 | pathogenic | Familial hypercholesterolemia 1 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
Color | RCV000775062 | SCV000909163 | pathogenic | Familial hypercholesterolemia | 2019-10-07 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000786355 | SCV001134247 | pathogenic | not provided | 2018-12-07 | criteria provided, single submitter | clinical testing | The best available variant frequency is uninformative. Statistically enriched in patients compared to controls. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. |
Integrated Genetics/Laboratory Corporation of America | RCV000775062 | SCV001363968 | pathogenic | Familial hypercholesterolemia | 2019-07-15 | criteria provided, single submitter | clinical testing | Variant summary: LDLR c.1285G>A (p.Val429Met) results in a conservative amino acid change located in the LDLR class B repeat domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251284 control chromosomes. c.1285G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Leitersdorf_1989, Versmissen_2011, Huijgen_2012, Bertolini_2013, Peng_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. This publication reported cells carrying the variant processed the LDL receptor protein more slowly and degraded the protein more rapidly compared to wild-type cells (Leitersdorf_1989). 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Brunham Lab, |
RCV000003882 | SCV001432624 | pathogenic | Familial hypercholesterolemia 1 | 2019-05-11 | criteria provided, single submitter | research | |
OMIM | RCV000003882 | SCV000024047 | pathogenic | Familial hypercholesterolemia 1 | 1993-12-01 | no assertion criteria provided | literature only | |
Cardiovascular Genetics Laboratory, |
RCV000003882 | SCV000268609 | pathogenic | Familial hypercholesterolemia 1 | 2011-11-07 | no assertion criteria provided | clinical testing | |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000003882 | SCV000606381 | pathogenic | Familial hypercholesterolemia 1 | no assertion criteria provided | research | ||
Stanford Center for Inherited Cardiovascular Disease, |
RCV000786355 | SCV000925141 | pathogenic | not provided | 2017-06-12 | no assertion criteria provided | provider interpretation | p.Val429Met (c.1285G>A; also known as Val408Met or V408M in the literature) in the LDLR gene (NM_000527.4) Given the strong case data for this founder variant, its location in the LDL receptor protein and its rarity in large population databases, we consider this variant disease-causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 204 unrelated cases of FH (not including this patient's family). There is very strong case data. There are likely many more cases of this variant given that it is a Dutch founder variant. This variant is classified as likely pathogenic or pathogenic by 6 submitters. It was seen in at least 34 individuals submitted by these groups, including 2 individuals from one family. This variant was found in a very large (8-generation, 412-member) Dutch family. 161 members of this family were found to have the variant and high cholesterol levels above the 95th percentile. Furthermore, this group identified a genotype-phenotype correlation: when V408M is maternally transmitted it is associated with a 2-fold increase in mortality risk in untreated individuals with FH. (Versmissen et al 2011). This variant was found in one out of 60 individuals from Ontario, Canada. This patient had Dutch ancestry. This variant was found in 2 of 1070 (of which 52 were homozygotes) Italian individuals with FH (Bertolini et al 2013). This variant was found in 1 Afrikans individual with homozygous FH (of Dutch ancestry), and these authors concluded that the p.Val429Met variant is a Dutch founder variant (Leitersdorf et al. 1989). This variant was identified in 1 of 25 German patients with FH. This variant was found in 4 of 28 individuals of Greek descent, ranging from 34 to 57 years old (Whittal et al 2009). This variant completely abolishes receptor function (Hobbs et al 1992). The valine at codon 429 is almost completely conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Val429Leu) nearby codons (p.Asn425Ile, p.Asn425Thrfs, p.Ala431Terfs, p.Ala431Pro, p.Ala431 Thr, p.Leu431Val, p.432Pro, p.Asp433del, p.Asp433Tyr, p.Asp433His). The variant was reported online in 3 of 123,065 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 1 of 15,391 individuals of South Asian descent (MAF=0.0032%), 1 of 12,290 individuals of Latino descent and 1 of 55,800 individuals of European (non-Finnish) descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). |