Submissions for variant NM_000527.5(LDLR):c.1105G>A (p.Val369Met)

gnomAD frequency: 0.00001  dbSNP: rs730882097

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001179374	SCV001344026	uncertain significance	Familial hypercholesterolemia	2022-03-03	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Val348Met in the mature protein) replaces valine with methionine at codon 369 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). A functional study has shown that this variant does not disrupt LDL uptake function of the LDLR protein (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 2/251362 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.
GeneDx	RCV000161979	SCV002567472	uncertain significance	not provided	2022-02-16	criteria provided, single submitter	clinical testing	Identified in association with early myocardial infarction and familial hypercholesterolemia (FH) in the published literature (Do et al., 2015; Li et al., 2017; Chan et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published in vitro functional studies showed no effect on LDL uptake (Thormaehlen et al., 2015); This variant is associated with the following publications: (PMID: 30592178, 27932355, 25647241, 25487149)
Fulgent Genetics, Fulgent Genetics	RCV002485006	SCV002790326	uncertain significance	Hypercholesterolemia, familial, 1	2021-09-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV002485006	SCV005427586	uncertain significance	Hypercholesterolemia, familial, 1	2024-02-22	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 369 of the LDLR protein. This variant is also known as p.Val348Met in the mature protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. A high-throughput functional study has shown that this variant does not disrupt LDL uptake (PMID: 25647241). This variant has been reported in one individual affected with familial hypercholesterolemia (PMID: 30592178). It has also been reported in one individual affected with early-onset myocardial infarction and in one healthy control (PMID: 25487149). This variant has been identified in 2/251362 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.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000161979	SCV000189554	not provided	not provided		no assertion provided	in vitro