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

gnomAD frequency: 0.00001  dbSNP: rs745343524

Total submissions: 6

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
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237891	SCV000606389	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research