Submissions for variant NM_000527.5(LDLR):c.811G>A (p.Val271Ile)

gnomAD frequency: 0.00001  dbSNP: rs749220643

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000172960	SCV005328524	uncertain significance	Hypercholesterolemia, familial, 1	2023-06-23	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.811G>A (p.Val271Ile) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP1, PP4, and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.00011 (0.011%) in East Asian exomes+genomes (gnomAD v2.1.1). BP4: REVEL=0.33. It is below 0.5, splicing evaluation required. Functional data on splicing not available. A) not on limits. B) does not create GT. C) there is no GT nearby. Variant is not predicted to alter splicing. PP1: Variant segregates with FH phenotype in 3 informative meioses in 1 family from PMID 26036859 (Brænne I et al., 2016). 2 affected family members have the variant. PP4: Variant meets PM2 and is identified in 1 index case with DLCN score >=6 from PMID 26036859 (Brænne I et al., 2016: LDL-C 286 mg/dl and a history of premature CAD, DLCN=7).
Institute for Integrative and Experimental Genomics, University of Luebeck	RCV000172960	SCV000212135	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV001190239	SCV001357686	likely benign	Familial hypercholesterolemia	2018-05-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003398872	SCV004121996	uncertain significance	not specified	2023-10-23	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.811G>A (p.Val271Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251456 control chromosomes. c.811G>A at a heterozygous state has been reported in the literature in several individuals affected with Hypercholesterolemia, or Coronary Aartery Disease and Myocardial Infarction with elevated low-density lipoprotein cholesterollevels (examples, Branne_2016, Huang_2020, Tomar_2022, Martin-Campos_2018). Particularly, Branne_2016 reported this variant in three siblings, two of whom were diagnosed with Coronary Aartery Disease and Myocardial Infarction, and the rest carrier remained unaffected with elevated LDLC levels. However, other studies evaluated this variant insignificant or Likely benign. These report(s) do not provide unequivocal conclusions about association of the variant with autosomal dominant or autosomal recessive 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: 26036859, 33994402, 30293936, 35130036). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001190239	SCV004453101	likely pathogenic	Familial hypercholesterolemia	2024-03-19	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 271 of the LDLR protein (p.Val271Ile). This variant is present in population databases (rs749220643, gnomAD 0.01%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 26036859, 29233637, 30293936, 33994402; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 189297). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LDLR protein function with a negative predictive value of 95%. 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.
All of Us Research Program, National Institutes of Health	RCV000172960	SCV004820217	likely benign	Hypercholesterolemia, familial, 1	2023-11-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004639157	SCV005135996	uncertain significance	Cardiovascular phenotype	2024-03-25	criteria provided, single submitter	clinical testing	The p.V271I variant (also known as c.811G>A), located in coding exon 5 of the LDLR gene, results from a G to A substitution at nucleotide position 811. The valine at codon 271 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in familial hypercholesterolemia (FH) cohorts; however, clinical details were limited in some cases (Brænne I et al. Eur J Hum Genet, 2016 Feb;24:191-7; Ma Y et al. J Clin Lipidol, 2018 Oct;12:230-235.e6; Martín-Campos JM et al. J Clin Lipidol, 2018 Sep;12:1452-1462; Razman AZ et al. Int J Mol Sci, 2022 Nov;23:[ePub ahead of print]). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.