Submissions for variant NM_000527.5(LDLR):c.1057G>A (p.Glu353Lys)

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237927	SCV000295172	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000237927	SCV000588545	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000775052	SCV000821458	uncertain significance	Familial hypercholesterolemia	2022-09-13	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 353 of the LDLR protein (p.Glu353Lys). This variant is present in population databases (rs370471092, gnomAD 0.03%). This missense change has been observed in individual(s) with familial hypercholesterolemia and myocardial infarction (PMID: 11810272, 15823288, 20506408, 25647241, 27828139, 27878139, 30971288). This variant is also known as p.Glu332Lys. ClinVar contains an entry for this variant (Variation ID: 161275). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR function (PMID: 25647241). 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.
Color Diagnostics, LLC DBA Color Health	RCV000775052	SCV000909152	uncertain significance	Familial hypercholesterolemia	2023-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 353 of the LDLR protein. This variant is also known as p.Glu332Lys in the mature protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. A functional study using transfected HeLa cells has shown inconclusive results regarding this variant's impact on LDLR expression (PMID: 25647241). This variant has been reported in four individuals affected with familial hypercholesterolemia (PMID: 11810272, 15823288, 20506408, 33994402, 34998859), as well as in one individual affected with premature myocardial infarction (PMID: 30971288). This variant has been identified in 16/281978 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.
Ambry Genetics	RCV002399518	SCV002713861	uncertain significance	Cardiovascular phenotype	2024-06-11	criteria provided, single submitter	clinical testing	The p.E353K variant (also known as c.1057G>A), located in coding exon 7 of the LDLR gene, results from a G to A substitution at nucleotide position 1057. The glutamic acid at codon 353 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in familial hypercholesterolemia (FH) cohorts (Fouchier SW et al. Hum Genet, 2001 Dec;109:602-15; Huijgen R et al. Hum Mutat, 2010 Jun;31:752-60; Chiou KR et al. J Clin Lipidol 2017 Jan;11:386-393.e6). 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.
Fulgent Genetics, Fulgent Genetics	RCV000237927	SCV002784200	uncertain significance	Hypercholesterolemia, familial, 1	2021-11-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000237927	SCV004820261	uncertain significance	Hypercholesterolemia, familial, 1	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Glu332Lys in the mature protein) replaces glutamic acid with lysine at codon 353 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 11810272, 15823288, 20506408; Huang et al, 2021, doi.org/10.5551/jat.62773), as well as in an individual affected with premature myocardial infarction (PMID: 30971288). This variant has also been identified in 16/281978 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000775052	SCV005381169	likely pathogenic	Familial hypercholesterolemia	2024-08-13	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1057G>A (p.Glu353Lys) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 250574 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (6e-05 vs 0.0013), allowing no conclusion about variant significance. c.1057G>A has been reported in the literature in the heterozygous state in multiple individuals affected with Familial Hypercholesterolemia (example, Kusters_2013, Pillai_2022, Reijman_2023) however it has also been observed in at least 1 person with a history of myocardial infarction but no significant elevation in LDL-C (example, Thormaehlen_2015). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity and was considered an "unclear" result by the authors (example, Thormaehlen_2015). The following publications have been ascertained in the context of this evaluation (PMID: 23833242, 34998859, 36752612, 25647241). ClinVar contains an entry for this variant (Variation ID: 161275). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000161978	SCV000189553	not provided	not provided		no assertion provided	in vitro
CSER _CC_NCGL, University of Washington	RCV002051668	SCV000190295	uncertain significance	Hypercholesterolemia	2014-06-01	no assertion criteria provided	research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237927	SCV000606304	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV000775052	SCV001460265	uncertain significance	Familial hypercholesterolemia	2020-09-16	no assertion criteria provided	clinical testing
Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham	RCV000775052	SCV005205795	uncertain significance	Familial hypercholesterolemia	2023-05-02	no assertion criteria provided	clinical testing	This missense change has been observed in individual(s) with familial hypercholesterolemia and myocardial infarction .This variant replaces glutamic acid with lysine at codon 353 of the LDLR protein.