Submissions for variant NM_000527.5(LDLR):c.1816G>A (p.Ala606Thr)

dbSNP: rs72658865

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238082	SCV002817165	uncertain significance	Hypercholesterolemia, familial, 1	2022-05-08	reviewed by expert panel	curation	The NM_000527.5 (LDLR): c. 1816G>A (p.Ala606Thr) variant is classified as Uncertain significance -insufficient evidence for Familial Hypercholesterolemia as no evidence codes were met as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 not Met: PopMax MAF = 0.0002024 in Latino population in gnomAD (gnomAD v2.1.1), and PopMAX MAF = 0.00043 in Latino population in ExAC (ExAC v0.3.1). PP3 not Met: REVEL = 0.725, which is below 0.75. Functional data on splicing is not available, in silico splicing prediction is required. The variant is exonic and located at least 50 bases downstream of authentic acceptor site, but it does not create GT. The variant is not on limit creating de novo acceptor site. Therefore, this variant is not predicted to alter splicing. BP4 not applicable: REVEL score for this variant is not below 0.5, BP4 is not applicable. PP4, PS4 not applicable: Variant did not meet PM2. PM5 not met: There are two other variants in same codon: LDLR: NM_000527:c1816G>T (p.Ala606Ser), LDLR: NM_000527:c.1817C>A (p.Ala606Asp), which are classified as Uncertain significance by these guidelines. Therefore PM5 is not met.
LDLR-LOVD, British Heart Foundation	RCV000238082	SCV000295674	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000238082	SCV000540901	likely benign	Hypercholesterolemia, familial, 1	2017-03-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000775078	SCV000909181	likely pathogenic	Familial hypercholesterolemia	2023-09-11	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 606 of the LDLR protein. This variant is also known as p.Ala585Thr in the mature protein. This variant alters a conserved alanine residue in the LDLR type B repeat 5 of the EGF precursor homology domain of the LDLR protein (a.a. 572 - 615), where pathogenic missense variants are found enriched (ClinVar-LDLR). 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 at least 10 individuals affected with familial hypercholesterolemia (PMID: 17087781, 19318025, 27784735, 29233637, 30293936, 32660911), including in cases of severe familial hypercholesterolemia in the homozygous state and compound heterozygous state with a second pathogenic variant (PMID: 11484166, 29233637). This variant has been identified in 9/251476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000775078	SCV000949990	uncertain significance	Familial hypercholesterolemia	2019-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with threonine at codon 606 of the LDLR protein (p.Ala606Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs72658865, ExAC 0.04%). This variant has been observed in individuals affected with familial hypercholesterolemia (PMID: 23340035, 19318025). This variant is also known as p.Ala585Thr in the literature. ClinVar contains an entry for this variant (Variation ID: 252046). 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: "Tolerated"; PolyPhen-2: "Possibly 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.
Ambry Genetics	RCV002411092	SCV002711992	uncertain significance	Cardiovascular phenotype	2022-01-27	criteria provided, single submitter	clinical testing	The p.A606T variant (also known as c.1816G>A), located in coding exon 12 of the LDLR gene, results from a G to A substitution at nucleotide position 1816. The alanine at codon 606 is replaced by threonine, an amino acid with similar properties. This alteration, which is also known as p.A585T, has been reported in familial hypercholesterolemia (FH) cohorts; however, clinical details were limited in some cases (Chiu CY et al. Metabolism, 2005 Aug;54:1082-6; Alonso R et al. Clin Biochem, 2009 Jun;42:899-903; Viladés Medel D et al. Am. J. Cardiol., 2013 Apr;111:955-61; Sánchez-Hernández RM et al. Circ Cardiovasc Genet, 2016 Dec;9:504-510; Ibarretxe D et al. Atherosclerosis, 2018 11;278:210-216; Ma Y et al. J Clin Lipidol 2018 Oct;12:230-235.e6; Lamiquiz-Moneo I et al. Rev Esp Cardiol (Engl Ed), 2021 Aug;74:664-673). 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.
GeneDx	RCV003233513	SCV003930909	likely pathogenic	not provided	2023-04-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32719484, 28502495, 23340035, 19020990, 30312929, 19318025, 30108616, 11484166, 7903864, 29233637, 32660911, 16092059, 34815205, 35725860, 27784735)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003993908	SCV004813642	uncertain significance	not specified	2024-02-05	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1816G>A (p.Ala606Thr) results in a non-conservative amino acid change in 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 3.6e-05 in 251476 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1816G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia and undertaking genetic testing based on familial/personal hypercholesterolemia (examples, Alonso_2009, Medel_2012, Velilla_2022), not all of which has provided sufficient information for analysis. These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19318025, 23340035, 36105085). ClinVar contains an entry for this variant (Variation ID: 252046). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000775078	SCV002086850	uncertain significance	Familial hypercholesterolemia	2020-10-15	no assertion criteria provided	clinical testing