Submissions for variant NM_000527.5(LDLR):c.508G>A (p.Asp170Asn)

gnomAD frequency: 0.00001  dbSNP: rs139089530

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Biomarker Research Laboratory, Mayo Clinic	RCV000211593	SCV000266315	uncertain significance	Hypercholesterolemia, familial, 1	2016-08-31	criteria provided, single submitter	research	MAF =<0.3%, likely pathogenic based on the integrative in-silico score; LDL-C >=160 mg/dL
Color Diagnostics, LLC DBA Color Health	RCV001190232	SCV001357679	uncertain significance	Familial hypercholesterolemia	2023-03-22	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Asp149Asn in the mature protein) replaces aspartic acid with asparagine at codon 170 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 an individual affected with familial hypercholesterolemia (PMID: 28145427). This variant has been identified in 3/251270 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	RCV000211593	SCV004820174	uncertain significance	Hypercholesterolemia, familial, 1	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Asp149Asn in the mature protein) replaces aspartic acid with asparagine at codon 170 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 not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 3/251270 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526645	SCV005039161	uncertain significance	not specified	2024-03-25	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.508G>A (p.Asp170Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251270 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.508G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia without evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36752612, 28145427, 33079599). ClinVar contains an entry for this variant (Variation ID: 224617). Based on the evidence outlined above, the variant was classified as uncertain significance.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211593	SCV000268567	uncertain significance	Hypercholesterolemia, familial, 1	2011-10-07	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211593	SCV000606140	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research