Submissions for variant NM_000527.5(LDLR):c.1285G>A (p.Val429Met)

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute for Integrative and Experimental Genomics,University of Luebeck	RCV000003882	SCV000212137	likely pathogenic	Familial hypercholesterolemia 1		criteria provided, single submitter	research
LDLR-LOVD, British Heart Foundation	RCV000003882	SCV000295341	likely pathogenic	Familial hypercholesterolemia 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute,Western University	RCV000003882	SCV000484726	likely pathogenic	Familial hypercholesterolemia 1		criteria provided, single submitter	clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	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,Centre for Cardiovascular Surgery and Transplantation	RCV000003882	SCV000540808	likely pathogenic	Familial hypercholesterolemia 1	2016-11-05	criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000003882	SCV000583816	pathogenic	Familial hypercholesterolemia 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	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	2020-11-02	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,Fulgent Genetics	RCV000003882	SCV000894174	pathogenic	Familial hypercholesterolemia 1	2018-10-31	criteria provided, single submitter	clinical testing
Color Health, Inc	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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, Centre for Heart and Lung Innovation,University of British Columbia	RCV000003882	SCV001432624	pathogenic	Familial hypercholesterolemia 1	2019-05-11	criteria provided, single submitter	research
Mayo Clinic Laboratories, Mayo Clinic	RCV000786355	SCV001715487	pathogenic	not provided	2021-02-24	criteria provided, single submitter	clinical testing	PP1_Strong, PS4_moderate, PS3_moderate, PM3, PP3, PP4
GeneDx	RCV000786355	SCV001797047	pathogenic	not provided	2019-12-05	criteria provided, single submitter	clinical testing	Described as being one of the two founder mutations, FH Afrikaner-2 (FH2), that account for approximately 80% of FH cases in the Afrikaner population (Kotze et al., 1993); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported as pathogenic/likely pathogenic by other clinical laboratories in ClinVar (ClinVar Variant ID# 3694; Landrum et al., 2016); Published functional studies demonstrate a damaging effect with slower processing of precursor LDLR protein to the mature protein and faster degradation of the protein (Leitersdorf et al., 1989); This variant is associated with the following publications: (PMID: 32719484, 33303402, 32041611, 30241732, 9763532, 15256764, 7649549, 11325764, 2569482, 8399083, 21722902, 15199436, 28492532, 19837725, 11196104, 11139254, 11668627, 21475731, 1952806, 8096412, 7903269, 26036859, 7718024, 8478013, 21925660, 23375686, 25741868, 20506408, 22390909)
OMIM	RCV000003882	SCV000024047	pathogenic	Familial hypercholesterolemia 1	1993-12-01	no assertion criteria provided	literature only
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000003882	SCV000268609	pathogenic	Familial hypercholesterolemia 1	2011-11-07	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000003882	SCV000606381	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research
Stanford Center for Inherited Cardiovascular Disease, Stanford University	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).
GenomeConnect - Invitae Patient Insights Network	RCV000775062	SCV001749524	not provided	Familial hypercholesterolemia		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 06-19-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.