Submissions for variant NM_000527.5(LDLR):c.148G>A (p.Ala50Thr)

dbSNP: rs137853960

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238452	SCV005688685	uncertain significance	Hypercholesterolemia, familial, 1	2024-10-28	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.148G>A (p.Ala50Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying no ACMG/AMP evidence codes as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on October 28th, 2024.
LDLR-LOVD, British Heart Foundation	RCV000238452	SCV000294486	likely benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455469	SCV000539517	uncertain significance	not specified	2016-08-12	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in probands, but no segregation data; ClinVar: 1 LB, 1 VUS
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985762	SCV001134252	uncertain significance	not provided	2024-10-22	criteria provided, single submitter	clinical testing	The LDLR c.148G>A (p.Ala50Thr) variant (also known as A29T) has been reported in the published literature in individuals with familial hypercholesterolemia (PMIDs: 17347910 (2007), 10422804 (1999), 30293936 (2018)). The frequency of this variant in the general population, 0.00068 (17/24956 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV001191123	SCV001358822	uncertain significance	Familial hypercholesterolemia	2023-03-08	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Ala29Thr in the mature protein) replaces alanine with threonine at codon 50 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 individuals affected with familial hypercholesterolemia (PMID: 17347910, 10422804, 30293936). This variant has been identified in 21/282594 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002392739	SCV002698726	benign	Cardiovascular phenotype	2022-08-11	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001191123	SCV003333690	likely benign	Familial hypercholesterolemia	2025-01-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000238452	SCV004820121	uncertain significance	Hypercholesterolemia, familial, 1	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Ala29Thr in the mature protein) replaces alanine with threonine at codon 50 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 individuals affected with familial hypercholesterolemia (PMID: 17347910, 10422804, 30293936). This variant has been identified in 21/282594 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Natera, Inc.	RCV001191123	SCV001456137	uncertain significance	Familial hypercholesterolemia	2020-09-16	no assertion criteria provided	clinical testing