Submissions for variant NM_000527.5(LDLR):c.988A>C (p.Asn330His)

gnomAD frequency: 0.00002  dbSNP: rs730882095

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001179373	SCV001344024	uncertain significance	Familial hypercholesterolemia	2022-12-09	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Asn309His in the mature protein) replaces asparagine with histidine at codon 330 of the LDLR protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). In a high-throughput LDL uptake assay, this variant has been determined to be non-disruptive to LDLR function (PMID: 25647241). To our knowledge, this variant has not been reported in individuals affected with LDLR-related disorders in the literature. This variant has been identified in 6/282428 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.
All of Us Research Program, National Institutes of Health	RCV003998538	SCV004820245	uncertain significance	Hypercholesterolemia, familial, 1	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Asn309His in the mature protein) replaces asparagine with histidine at codon 330 of the LDLR protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. In a high-throughput LDL uptake assay, this variant has been determined to be non-disruptive to LDLR function (PMID: 25647241). To our knowledge, this variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 6/282428 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000161975	SCV000189550	not provided	not provided		no assertion provided	in vitro