ClinVar Genomic variation as it relates to human health

The NM_000527.5(LDLR):c.232C>T (p.Arg78Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4_Supporting and PP4) 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: PM2 - PopMax MAF = 0.0001002 (0.010%) in South Asian exomes (gnomAD v2.1.1). PP4 - Variant meets PM2. Identified in 2 FH cases from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with Dutch Lipid Clinic score ≥ 6. PS4_supporting - Variant meets PM2. Variant identified in at least 4 unrelated index cases with Simon-Broome criteria for FH or Dutch Lipid Clinic score equal or above 6 from different labs.

The c.232C>T (p.R78C) alteration is located in exon 3 (coding exon 3) of the LDLR gene. This alteration results from a C to T substitution at nucleotide position 232, causing the arginine (R) at amino acid position 78 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

The p.Arg78Cys variant in LDLR has been reported in at least 9 individuals with familial hypercholesterolemia (PMID: 9259195, 28502495, 11845603, 9664576, 22883975, 24956927, 27680772) and has been Identified in 0.01002% (2/19952) of East Asian chromosomes, and at lower frequencies in other populations, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs370860696). This variant has also been reported in ClinVar (VariationID: 161289) as likely pathogenic by the British Heart Foundation, pathogenic by Fiona Stanley Hospital, and as a VUS by the University of Washington Medical Center. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_moderate (Richards 2015).

This sequence change replaces arginine with cysteine at codon 78 of the LDLR protein (p.Arg78Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs370860696, ExAC 0.01%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 9237502, 9259195, 9664576, 22883975, 22910581, 24956927). This variant is also known as R57C. ClinVar contains an entry for this variant (Variation ID: 161289). 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: "Deleterious"; PolyPhen-2: "Probably 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.

This missense variant (also known as p.Arg57Cys in the mature protein) replaces arginine with cysteine at codon 78 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 individuals affected with familial hypercholesterolemia (PMID: 9259195, 9664576, 24956927, 32522009). This variant has been identified in 8/282882 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.

This missense variant (also known as p.Arg57Cys in the mature protein) replaces arginine with cysteine at codon 78 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 individuals affected with familial hypercholesterolemia (PMID: 9259195, 9664576, 24956927, 32522009). This variant has been identified in 8/282882 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.

The LDLR p.Arg78Cys variant was identified in 2 of 1606 proband chromosomes (frequency: 0.001) from individuals with familial hypercholesterolemia (FH) (Callis_1998_PMID:9664576; Day_1997_PMID:9259195). The variant was also identified in 1 of 232 individuals from a Scottish cohort with moderately high total cholesterol despite cholesterol-lowering therapy but was not identified in 192 controls or 193 individuals with high cholesterol (Norsworthy_2014_PMID:24956927). In a family with FH, the p.A78C variant was identified in the mother with classical heterozygous FH who also carried a deletion of exons 2-5 of the LDLR gene. The father carried the exon 2-5 deletion as well as another intronic LDLR variant and also presented with classical heterozygous FH. The child was homozygous for the exon 2-5 deletion and presented with classical homozygous FH, suggesting that the exon 2-5 deletion was the cause of disease in this family and that the p.A78C variant likely does not contribute to disease in the mother (Jelassi_2012_PMID:22910581). The variant was identified in dbSNP (ID: rs370860696), LOVD 3.0 and ClinVar (classified as a VUS by CSER_CC_NCGL; University of Washington Medical Center, likely pathogenic by LDLR-LOVD, British Heart Foundation and pathogenic by Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital). The variant was identified in control databases in 8 of 282882 chromosomes at a frequency of 0.000028 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 2 of 19952 chromosomes (freq: 0.0001), South Asian in 2 of 30616 chromosomes (freq: 0.000065), African in 1 of 24968 chromosomes (freq: 0.00004) and European (non-Finnish) in 3 of 129190 chromosomes (freq: 0.000023), but was not observed in the Latino, Ashkenazi Jewish, European (Finnish) or Other populations. The p.Arg78 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.