Submissions for variant NM_000527.5(LDLR):c.2072C>T (p.Ser691Leu)

gnomAD frequency: 0.00005  dbSNP: rs369943481

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000455095	SCV000540856	uncertain significance	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001192331	SCV001360363	uncertain significance	Familial hypercholesterolemia	2024-04-18	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 691 of the LDLR protein. This variant is also known as p.Ser670Leu in the mature protein. 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 at least two individuals affected with familial hypercholesterolemia (PMID: 28379029, 28965616). This variant has been identified in 8/282600 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.
Mendelics	RCV000455095	SCV002517308	likely pathogenic	Hypercholesterolemia, familial, 1	2022-05-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001192331	SCV002958968	uncertain significance	Familial hypercholesterolemia	2022-08-30	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 691 of the LDLR protein (p.Ser691Leu). This variant is present in population databases (rs369943481, gnomAD 0.02%). This missense change has been observed in individual(s) with hypercholesterolemia (PMID: 28379029, 28965616; Invitae). ClinVar contains an entry for this variant (Variation ID: 403644). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant disrupts the p.Ser691 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 32770674), which suggests that this may be a clinically significant amino acid residue. 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.
All of Us Research Program, National Institutes of Health	RCV000455095	SCV004818493	uncertain significance	Hypercholesterolemia, familial, 1	2024-08-06	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Ser670Leu in the mature protein) replaces serine with leucine at codon 691 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 individuals affected with familial hypercholesterolemia (PMID: PMID: 28379029, 28965616). This variant has been identified in 8/282600 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	RCV004639237	SCV005136002	uncertain significance	Cardiovascular phenotype	2024-03-21	criteria provided, single submitter	clinical testing	The p.S691L variant (also known as c.2072C>T), located in coding exon 14 of the LDLR gene, results from a C to T substitution at nucleotide position 2072. The serine at codon 691 is replaced by leucine, an amino acid with dissimilar properties. This variant co-occurred with a second LDLR variant in an individual with familial hypercholesterolemia (FH), and was also detected in an additional individual from a different FH cohort; however, clinical details were limited (Pirillo A et al. Atheroscler Suppl, 2017 Oct;29:17-24; Tichý L et al. Physiol Res, 2017 Apr;66:S47-S54). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005056007	SCV005725695	uncertain significance	not specified	2024-11-26	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.2072C>T (p.Ser691Leu) results in a non-conservative amino acid change located in the Epidermal growth factor-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251196 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2072C>T has been reported in the literature in individuals affected with hypercholesterolemia (example: Tichy_2017, Pirillo_2017, Trinder_2020, Gratton_2023, Internal data). These data do not allow any conclusion about variant significance. 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: 28965616, 28379029, 33079599, 37409534, No_PMID).ClinVar contains an entry for this variant (Variation ID: 403644). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV005250051	SCV005900873	uncertain significance	not provided	2024-09-17	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 28379029, 28965616)