Submissions for variant NM_000527.5(LDLR):c.440C>T (p.Thr147Ile)

dbSNP: rs879254524

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237461	SCV004022432	likely pathogenic	Hypercholesterolemia, familial, 1	2023-04-28	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.440C>T (p.Thr147Ile) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3_Supporting, PM1, PM2, and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS3_Supporting: Level 3 assays: PMID 21865347: Htz Patient lymphocytes, FACS assays - results - 55-70% LDLR activity ---- results are below 85% of wild-type activity. So PS3_Supporting is met. PM1: Variant meets PM2 and is on exon 4. So PM1 is met. PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So PM2 is met. PP3: REVEL = 0.811. It is above 0.75, so PP3 is met.
LDLR-LOVD, British Heart Foundation	RCV000237461	SCV000294710	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000237461	SCV000599332	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	curation
Color Diagnostics, LLC DBA Color Health	RCV001186868	SCV001353458	likely pathogenic	Familial hypercholesterolemia	2023-02-16	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Thr126Ile in the mature protein) replaces threonine with isoleucine at codon 147 in the LDLR type A repeat 4 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in a partial loss of LDLR function (PMID: 21865347). Threonine at this position is located in a functionally important region, and missense variants at this position are expected to interrupt glycosylation of linker regions in LDLR (PMID: 24798328). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 21865347, 34297352; Color internal data; communication with an external laboratory; ClinVar SCV002633357.1). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000237461	SCV001653593	pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing	Reduced activity in functional assays.
AiLife Diagnostics, AiLife Diagnostics	RCV002223826	SCV002502824	likely pathogenic	not provided	2021-12-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002327173	SCV002633357	likely pathogenic	Cardiovascular phenotype	2021-09-13	criteria provided, single submitter	clinical testing	The p.T147I variant (also known as c.440C>T), located in coding exon 4 of the LDLR gene, results from a C to T substitution at nucleotide position 440. The threonine at codon 147 is replaced by isoleucine, an amino acid with similar properties. This alteration was reported in two individuals from a familial hypercholesterolemia cohort and shown to reduce LDLR activity to 56% of normal levels in vivo (Romano M et al. J. Lipid Res., 2011 Nov;52:2095-100). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000237461	SCV003932171	likely pathogenic	Hypercholesterolemia, familial, 1	2023-03-06	criteria provided, single submitter	clinical testing	PS3, PM2, PS4_Moderate, PP3