Submissions for variant NM_000527.5(LDLR):c.1981C>A (p.Pro661Thr)

gnomAD frequency: 0.00001  dbSNP: rs1182317785

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Fundacion Hipercolesterolemia Familiar	RCV000509512	SCV000607661	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV001805127	SCV002052016	uncertain significance	Familial hypercholesterolemia	2022-12-05	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Pro640Thr in the mature protein) replaces proline with threonine at codon 661 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: 28475941). 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	RCV001805127	SCV002116130	likely pathogenic	Familial hypercholesterolemia	2024-08-19	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 661 of the LDLR protein (p.Pro661Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 28475941, 34456049; Invitae). ClinVar contains an entry for this variant (Variation ID: 441225). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Pro661 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 35047021), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002420291	SCV002722923	uncertain significance	Cardiovascular phenotype	2021-03-23	criteria provided, single submitter	clinical testing	The p.P661T variant (also known as c.1981C>A), located in coding exon 13 of the LDLR gene, results from a C to A substitution at nucleotide position 1981. The proline at codon 661 is replaced by threonine, an amino acid with highly similar properties. This variant has been reported in a hypercholesterolemia cohort; however, clinical details were limited (Bourbon M et al. Atherosclerosis, 2017 07;262:8-13). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV000509512	SCV004818480	uncertain significance	Hypercholesterolemia, familial, 1	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Pro640Thr in the mature protein) replaces proline with threonine at codon 661 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: 28475941). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701579	SCV005203108	uncertain significance	not specified	2024-07-09	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1981C>A (p.Pro661Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251432 control chromosomes. c.1981C>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia (e.g. Marco-Bened_2022, Bourbon_2017). These data indicate that the variant may be associated with disease. 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: 28475941, 34456049). ClinVar contains an entry for this variant (Variation ID: 441225). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.