Submissions for variant NM_000527.5(LDLR):c.1529C>T (p.Thr510Met)

gnomAD frequency: 0.00002  dbSNP: rs755154048

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237591	SCV005375300	uncertain significance	Hypercholesterolemia, familial, 1	2024-08-30	reviewed by expert panel	curation	The NM_000527.5 (LDLR): c.1529C>T (p.Thr510Met) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 30 August 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.00002228 (0.002228%) in East Asian exomes (gnomAD v4.1.0). PP3 - REVEL = 0.85. PS4_supporting, PP4: Variant meets PM2 and was identified in 4 unrelated index cases (1 case with DLCN score >=6 from Robarts Research Institute, Canada; 1 case meeting Simon Broome criteria from PMID 10947889 (Tonstad et al., 2000), Norway; 1 case with possible FH by MedPed criteria from PMID 22698793 (Tichý et al., 2012), Czech Republic; 1 case with clinical diagnosis of definite FH, probable FH or severe hypercholesterolemia according to the Canadian definition of FH from PMID 37607748 (Guerin et al., 2023), Canada].
LDLR-LOVD, British Heart Foundation	RCV000237591	SCV000295484	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000237591	SCV000540811	likely pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001177034	SCV001341144	uncertain significance	Familial hypercholesterolemia	2019-04-02	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Thr489Met in the mature protein) is located in the third LDLR type B repeat of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in three individuals affected with familial hypercholesterolemia (PMID: 16542394, 22698793). This variant has also been identified in 4/246252 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001177034	SCV001379760	uncertain significance	Familial hypercholesterolemia	2021-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with methionine at codon 510 of the LDLR protein (p.Thr510Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs755154048, ExAC 0.02%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 15199436, 16542394, 22698793). This variant is also known as T489M. ClinVar contains an entry for this variant (Variation ID: 251886). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000237591	SCV001422918	uncertain significance	Hypercholesterolemia, familial, 1	2020-01-22	criteria provided, single submitter	curation	The p.Thr510Met variant in LDLR has been reported in 8 individuals (5 Norwegian, 2 Danish, 1 Czech) with Familial Hypercholesterolemia, segregated with disease in 5 affected relatives from 1 family (PMID: 15199436, 22698793, 16542394), and has been identified in 0.005782% (2/34592) of Latino chromosomes and 0.0008793% (1/113732) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs755154048). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 251886). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP1_Moderate, PP3, PS4_Supporting (Richards 2015).
Institute of Human Genetics, University of Leipzig Medical Center	RCV000237591	SCV001440425	likely pathogenic	Hypercholesterolemia, familial, 1	2022-12-06	criteria provided, single submitter	clinical testing	_x000D_In the same patient the variant NM_000527.5:c.798T>A was identified. Criteria applied: PS4_MOD, PP1_MOD, PM2_SUP, PP3
Ambry Genetics	RCV002401935	SCV002708239	uncertain significance	Cardiovascular phenotype	2022-06-10	criteria provided, single submitter	clinical testing	The p.T510M variant (also known as c.1529C>T), located in coding exon 10 of the LDLR gene, results from a C to T substitution at nucleotide position 1529. The threonine at codon 510 is replaced by methionine, an amino acid with similar properties. This alteration, which is also known as p.T489M, has been reported in several familial hypercholesterolemia (FH) cohorts; however, clinical details were limited (Tonstad S et al. J Intern Med, 2000 Aug;248:111-8; Brusgaard K et al. Clin Genet, 2006 Mar;69:277-83; Tichý L et al. Atherosclerosis, 2012 Aug;223:401-8; Lamiquiz-Moneo I et al. Rev Esp Cardiol (Engl Ed), 2021 Aug;74:664-673; Rieck L et al. Clin Genet, 2020 11;98:457-467). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV000237591	SCV004822470	uncertain significance	Hypercholesterolemia, familial, 1	2024-07-20	criteria provided, single submitter	clinical testing	This missense variant replacesthreonine with methionine at codon 510 of the LDLR protein. This variant is also known as p.Thr489Met in the mature protein. This variant alters a conserved threonine residue in the LDLR type B repeat 3 of the LDLR protein (a.a. 486-528), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 15199436, 16542394, 22698793, 32660911, 32770674, 33740630) and in an individual affected with isolated hypercholesterolemia (PMID: 33303402). This variant has been identified in 4/251450 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017558	SCV004848123	uncertain significance	not provided	2019-04-05	criteria provided, single submitter	clinical testing	The p.Thr510Met variant in LDLR has been reported in 4 individuals with hypercholesterolemia (Lered 2004, Brusgaard 2006, Tichy 2012) and has also been reported in ClinVar (Variation ID# 251886). This variant has also been identified in 1/33582 Latino chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org; dbSNP rs755154048). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Thr510Met variant is uncertain. The ACMG/AMP Criteria applied: PM2, PS4_Supporting.
Natera, Inc.	RCV001177034	SCV002086429	uncertain significance	Familial hypercholesterolemia	2020-10-29	no assertion criteria provided	clinical testing