ClinVar Genomic variation as it relates to human health

The NM_000527.5(LDLR):c.967G>A (p.Gly323Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PP3 - REVEL = 0.871.

The p.Gly323Ser variant in LDLR has been reported in at least 2 individuals (including 1 Danish individual) with Familial Hypercholesterolemia (PMID: 15823288, 25637381), and has been identified in 0.02008% (5/24906) of African chromosomes and 0.003267% (1/30606) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs373869746). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. 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 as a VUS and a likely pathogenic variant in ClinVar (Variation ID: 161282). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Gly323Ser variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting (Richards 2015).

In the published literature, this variant has been reported in individuals with familial hypercholesterolemia (PMIDs: 15823288 (2005), 34176852 (2021), 35480308 (2022)). The frequency of this variant in the general population, 0.0002 (5/24906 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

The p.G323S variant (also known as c.967G>A), located in coding exon 7 of the LDLR gene, results from a G to A substitution at nucleotide position 967. The glycine at codon 323 is replaced by serine, an amino acid with similar properties. This alteration has been reported in familial hypercholesterolemia (FH) cohorts; however, clinical details were limited (Damgaard D et al. Atherosclerosis, 2005 May;180:155-60; Matsunaga K et al. J Atheroscler Thromb, 2022 Jun;29:839-849; Tada H et al. Front Genet, 2022 Apr;13:872056). This amino acid position is highly 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.

This missense variant replaces glycine with serine at codon 323 in the EGF-like repeat A in the EGF precursor homology domain of the LDLR protein. This variant is also known as p.Gly302Ser in the mature protein. Computational prediction suggests that this variant may have 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 individuals affected with familial hypercholesterolemia (PMID: 15823288, 34176852, 37967952; communication with an external laboratory: ClinVar SCV000503269.1, SCV003517112.1). This variant has been identified in 6/282324 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Gly323Cys, is known to be disease-causing (ClinVar variation ID: 375806), indicating that glycine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.

subject mutated among 2600 FH index cases screened = 1 / Software predictions: Damaging

This missense variant replaces glycine with serine at codon 323 in the EGF-like repeat A in the EGF precursor homology domain of the LDLR protein. This variant is also known as p.Gly302Ser in the mature 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 individuals affected with familial hypercholesterolemia (PMID: 15823288, 34176852; communication with an external laboratory; ClinVar SCV000503269.1, SCV003517112.1). This variant has been identified in 6/282324 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Gly323Cys, is known to be disease-causing (ClinVar variation ID: 375806), indicating that glycine at this position is important for LDLR protein function. Although there is a suspicion that p.Gly323Ser may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Variant summary: LDLR c.967G>A (p.Gly323Ser) results in a non-conservative amino acid change located in the EGFlike 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 1.2e-05 in 250956 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.967G>A has been reported in the literature in individuals from familial hypercholesterolemia (FH) cohorts (example: Damgaard_2005, Amendola_2015Tada_2022, Matsunga_2022, Gratton_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. The following publications have been ascertained in the context of this evaluation (PMID: 25637381, 15823288, 37409534, 34176852, 35480308). ClinVar contains an entry for this variant (Variation ID: 161282). Based on the evidence outlined above, the variant was classified as uncertain significance.

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 323 of the LDLR protein (p.Gly323Ser). This variant is present in population databases (rs373869746, gnomAD 0.03%). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 15823288; Invitae). This variant is also known as G302S. ClinVar contains an entry for this variant (Variation ID: 161282). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.