ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1078G>C (p.Asp360His) (rs777926251)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Iberoamerican FH Network RCV000627169 SCV000748048 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Color Health, Inc RCV000775610 SCV000909974 uncertain significance Familial hypercholesterolemia 2020-11-12 criteria provided, single submitter clinical testing 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.
Invitae RCV000775610 SCV001010068 likely benign Familial hypercholesterolemia 2020-12-05 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000627169 SCV001286366 uncertain significance Familial hypercholesterolemia 1 2019-04-18 criteria provided, single submitter clinical testing 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001199891 SCV001370646 uncertain significance not specified 2020-12-21 criteria provided, single submitter clinical testing 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 (examples-Ahmad_2012 and Hernandez Flores_2018, 2020). One study reports the variant to be associated with familial hypercholesterolemia (FH) in a consanguineous Mexican community, however complete sequencing of all FH-associated genes was not performed (Hernandez Flores_2020). These reports 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=1, VUS n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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