Submissions for variant NM_000527.5(LDLR):c.2050G>A (p.Ala684Thr)

gnomAD frequency: 0.00002  dbSNP: rs774730452

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237554	SCV000295842	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000237554	SCV000503453	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1 / previously described in association with FH (linked to ethnicity ?)/software prediction damaging
Labcorp Genetics (formerly Invitae), Labcorp	RCV001057854	SCV001222369	pathogenic	Familial hypercholesterolemia	2024-10-15	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 684 of the LDLR protein (p.Ala684Thr). This variant is present in population databases (rs774730452, gnomAD 0.02%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 11005141; internal data). This variant is also known as A663T. ClinVar contains an entry for this variant (Variation ID: 252192). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001057854	SCV001347392	uncertain significance	Familial hypercholesterolemia	2023-03-22	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Ala663Thr in the mature protein) replaces alanine with threonine at codon 684 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with familial hypercholesterolemia (PMID: 11005141, 26608663). This variant has been identified in 4/251258 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.
All of Us Research Program, National Institutes of Health	RCV000237554	SCV004818486	uncertain significance	Hypercholesterolemia, familial, 1	2024-03-05	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Ala663Thr in the mature protein) replaces alanine with threonine at codon 684 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two Asian individuals affected with familial hypercholesterolemia (PMID: 11005141, 26608663). This variant has been identified in 4/251258 chromosomes (4/18394 East Asian 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV004791372	SCV005408729	uncertain significance	not provided	2023-07-13	criteria provided, single submitter	clinical testing	PP3, PM2, PS4_supporting
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000237554	SCV005416389	uncertain significance	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3+PM3+PP4
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237554	SCV000606586	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV001057854	SCV002086861	uncertain significance	Familial hypercholesterolemia	2020-02-10	no assertion criteria provided	clinical testing