Submissions for variant NM_000527.5(LDLR):c.510C>A (p.Asp170Glu)

dbSNP: rs1060499931

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000455904	SCV005903132	likely pathogenic	Hypercholesterolemia, familial, 1	2025-03-09	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.510C>A (p.Asp170Glu) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 9 March 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.00002664 (0.002664%) in African/African American exomes (gnomAD v4.1.0). PM1: Variant meets PM2 and is missense in exon 4. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 2 unrelated index cases who fulfill Simon Broome criteria for possible FH (1 case from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic; 1 case meeting Simon Broome criteria for possible FH in PMID 27824480 (Gabcová et al., 2017)).
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000455904	SCV000540897	likely pathogenic	Hypercholesterolemia, familial, 1	2017-03-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001179533	SCV001344209	uncertain significance	Familial hypercholesterolemia	2020-04-27	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Asp149Glu in the mature protein) replaces aspartic acid with glutamic acid at codon 170 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 2 individuals affected with familial hypercholesterolemia in one family (PMID: 27824480). This variant has not been identified 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	RCV000455904	SCV005426451	uncertain significance	Hypercholesterolemia, familial, 1	2024-05-30	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Asp149Glu in the mature protein) replaces aspartic acid with glutamic acid at codon 170 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 2 individuals affected with familial hypercholesterolemia in one family (PMID: 27824480). This variant has not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001179533	SCV005744393	uncertain significance	Familial hypercholesterolemia	2024-11-28	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 170 of the LDLR protein (p.Asp170Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 27824480, 36229376). ClinVar contains an entry for this variant (Variation ID: 403662). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The glutamic 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.