Submissions for variant NM_000527.5(LDLR):c.656G>A (p.Gly219Asp)

gnomAD frequency: 0.00002  dbSNP: rs201384282

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238334	SCV000294856	likely benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000819529	SCV000960194	uncertain significance	Familial hypercholesterolemia	2021-08-30	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with aspartic acid at codon 219 of the LDLR protein (p.Gly219Asp). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs201384282, ExAC 0.003%). This missense change has been observed in individual(s) with hypercholesterolemia (PMID: 9678702, 15135252). This variant is also known as G198D. ClinVar contains an entry for this variant (Variation ID: 183137). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The aspartic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
All of Us Research Program, National Institutes of Health	RCV000238334	SCV004826081	uncertain significance	Hypercholesterolemia, familial, 1	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Gly198Asp in the mature protein) replaces glycine with aspartic acid at codon 219 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 using transfected HeLa cells has shown that this variant does not cause a significant decrease in LDLR activity (PMID: 25647241). This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 9678702). It has also been reported in a family affected with familial hypercholesterolemia and also carrying a different pathogenic variant in LDLR; this variant did not segregate with disease in multiple affected individuals (PMID: 15135252). This variant has been identified in 2/245584 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	RCV000162018	SCV000189621	not provided	not provided		no assertion provided	in vitro
Natera, Inc.	RCV000819529	SCV002086378	uncertain significance	Familial hypercholesterolemia	2021-02-24	no assertion criteria provided	clinical testing