ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1301C>T (p.Thr434Met)

gnomAD frequency: 0.00001  dbSNP: rs745343524
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000237891 SCV002817151 uncertain significance Hypercholesterolemia, familial, 1 2022-10-28 reviewed by expert panel curation The NM_000527.5(LDLR):c.1301C>T (p.Thr434Met) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, PP4, BP2, and BP4 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: PM2: PopMax MAF = 0.00007 (0.007%) in South Asian exomes+genomes (gnomAD v2.1.1). So PM2 is met. PM5: 3 other missense variants in the same codon: - NM_000527.5(LDLR):c.1301C>G (p.Thr434Arg) (ClinVar ID 251774) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.1300A>C (p.Thr434Pro)(ClinVar ID 496018) - Unknown significance by these guidelines - NM_000527.5(LDLR):c.1301C>A (p.Thr434Lys) (ClinVar ID 251773) - Likely pathogenic by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines. PP4: Variant meets PM2 and is identified in 1 case with DLCN criteria>=6 from Robarts Research Institue. So PP4 is met. BP2: 1 case with DLCN≥6 and LDL-C 7.44 mmol/l and NM_000384.3(APOB):c.10580G>A (p.Arg3527Gln) variant from Robarts Research Institue (The APOB variant, although not classified with FH VCEP approved guidelines, is considered Pathogenic by the FH VCEP). BP4: REVEL = 0.47. It is below 0.5. Splicing evaluation required. Functional data on splicing not available. A) variant not on limits. B) variant is exonic and at least 50bp upstream from the canonical donor site, but it doesn't create AG or GT. Variant is not predicted to alter splicing. So BP4 is met.
LDLR-LOVD, British Heart Foundation RCV000237891 SCV000295354 likely benign Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute, Western University RCV000237891 SCV000484722 uncertain significance Hypercholesterolemia, familial, 1 2019-08-22 criteria provided, single submitter clinical testing
Invitae RCV001044362 SCV001208156 uncertain significance Familial hypercholesterolemia 2022-11-01 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 434 of the LDLR protein (p.Thr434Met). This variant is present in population databases (rs745343524, gnomAD 0.006%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11668627, 15015036, 18325082, 23375686). This variant is also known as T413M. ClinVar contains an entry for this variant (Variation ID: 251775). 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. This variant disrupts the p.Thr434 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10634824, 21868016; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health RCV001044362 SCV001347904 likely benign Familial hypercholesterolemia 2018-11-11 criteria provided, single submitter clinical testing
Ambry Genetics RCV004020964 SCV005035975 uncertain significance Cardiovascular phenotype 2023-11-01 criteria provided, single submitter clinical testing The p.T434M variant (also known as c.1301C>T), located in coding exon 9 of the LDLR gene, results from a C to T substitution at nucleotide position 1301. The threonine at codon 434 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in familial hypercholesterolemia (FH) cohorts; however, clinical details were limited in some cases (Wang J et al. Hum Mutat, 2001 Oct;18:359; Mihaylov VA et al. J Hum Genet, 2004 Mar;49:173-176; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8). This amino acid position is poorly 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.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237891 SCV000606389 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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