ClinVar Genomic variation as it relates to human health

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Variant summary: LDLR c.1078G>C (p.Asp360His) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251310 control chromosomes, predominantly at a frequency of 0.0011 within the Latino subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Early Onset Coronary Artery Disease phenotype (0.001), suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.1078G>C has been reported in the literature in individuals affected with hypercholesterolemia, including in a family with 1 homozygous and 4 heterozygous affected individuals (e.g., Ahmad_2012, Vasquez-Cardenas_2016 (no PMID), Hernandez-Flores_2018, Hernandez-Flores_2020). Additionally, one study suggested the variant may represent a founder mutation in an isolated Mexican community, however this could not be conclusively confirmed as the study only utilized targeted genotyping (e.g., Hernandez-Flores_2020). These reports therefore do not provide unequivocal conclusions about association of the variant with Early Onset Coronary Artery Disease. 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: 23064986, 32113782, 29576406). Six submitters have reported this variant to ClinVar after 2014 with conflicting assessments (uncertain significance, n = 5; likely benign, n = 1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

This missense variant (also known as p.Asp339His in the mature protein) replaces aspartic acid with histidine at codon 360 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 over twenty heterozygous Hispanic individuals affected with hypercholesterolemia (PMID: 23064986, 29576406, 32113782) and in a homozygous individual affected with severe hypercholesterolemia and xanthoma (PMID: 29576406). However, this variant is common in the general population and has been identified in 43/282710 chromosomes (40/35438 Latino chromosomes; 0.1128%) by the Genome Aggregation Database (gnomAD). A study conducted in a Mexican population has reported that carriers of this variant show significantly higher LDL-C levels than non-carriers (PMID: 32113782). This study only looked for the presence of this variant in affected individuals and did not screen for other variants in the LDLR gene or other genes known to cause familial hypercholesterolemia. Therefore, it is not clear if this variant is responsible for the observed phenotype. 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.Asp339His in the mature protein) replaces aspartic acid with histidine at codon 360 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 over twenty heterozygous Hispanic individuals affected with hypercholesterolemia (PMID: 23064986, 29576406, 32113782) and in a homozygous individual affected with severe hypercholesterolemia and xanthoma (PMID: 29576406). However, this variant is common in the general population and has been identified in 43/282710 chromosomes (40/35438 Latino chromosomes; 0.1128%) by the Genome Aggregation Database (gnomAD). A study conducted in a Mexican population has reported that carriers of this variant show significantly higher LDL-C levels than non-carriers (PMID: 32113782). This study only looked for the presence of this variant in affected individuals and did not screen for other variants in the LDLR gene or other genes known to cause familial hypercholesterolemia. Therefore, it is not clear if this variant is responsible for the observed phenotype. 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 p.D360H variant (also known as c.1078G>C), located in coding exon 8 of the LDLR gene, results from a G to C substitution at nucleotide position 1078. The aspartic acid at codon 360 is replaced by histidine, an amino acid with similar properties. This variant was detected in a Mexican individual with homozygous familial hypercholesterolemia (FH), who had significant hypercholesterolemia with xanthoma and four heterozygous affected siblings (Hern&aacute;ndez Flores TJ et al. J Clin Lipidol Mar;12:693-701). This variant was also reported in a Hispanic female with elevated LDLc and history of ischemic stroke (Ahmad Z et al. Circ Cardiovasc Genet, 2012 Dec;5:666-75). Based on data from gnomAD, the C allele has an overall frequency of approximately 0.015% (43/282710) total alleles studied. The highest observed frequency was 0.113% (40/35438) of Latino alleles. This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.