Submissions for variant NM_000527.5(LDLR):c.1323C>T (p.Ile441=)

gnomAD frequency: 0.00134  dbSNP: rs5933

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000548668	SCV001960952	benign	Hypercholesterolemia, familial, 1	2021-06-23	reviewed by expert panel	curation	The NM_000527.4(LDLR):c.1323C>T (p.Ile441=) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes BS1, BS2, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BS1 - FAF = 0.003722 (0.37%) in African exomes (gnomAD v2.1.1). BS2 - Variant is observed in heterozygosity in 5 normolipidemic adults. BP4 - no REVEL, splicing evaluation required. No functional study performed. A) not on limits B) does not create GT C) no GT nearby. BP7 - Variant is synonymous and meets BP4.
Invitae	RCV000771544	SCV000627018	benign	Familial hypercholesterolemia	2024-01-31	criteria provided, single submitter	clinical testing
Robarts Research Institute, Western University	RCV000548668	SCV000782912	benign	Hypercholesterolemia, familial, 1	2018-01-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771544	SCV000904105	likely benign	Familial hypercholesterolemia	2017-07-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781494	SCV000919572	benign	not specified	2017-10-12	criteria provided, single submitter	clinical testing	Variant summary: The LDLR c.1323C>T (p.Ile441Ile) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 121/277028 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.004829 (116/24020). This frequency is about 4 times the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. An internal LCA sample also carried a pathogenic variant LDLR c.590G>A/ p.Cys197Tyr, further supporting the benign nature of this variant. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. Taken together, this variant is classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000781494	SCV001470527	benign	not specified	2019-11-22	criteria provided, single submitter	clinical testing
GeneDx	RCV001706662	SCV001826358	likely benign	not provided	2021-03-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002384049	SCV002689005	benign	Cardiovascular phenotype	2022-06-06	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.
PreventionGenetics, part of Exact Sciences	RCV003960265	SCV004778751	likely benign	LDLR-related disorder	2019-04-30	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
All of Us Research Program, National Institutes of Health	RCV000548668	SCV004820297	likely benign	Hypercholesterolemia, familial, 1	2024-02-05	criteria provided, single submitter	clinical testing
GENinCode PLC	RCV000771544	SCV005073990	benign	Familial hypercholesterolemia	2023-07-06	criteria provided, single submitter	clinical testing