Submissions for variant NM_000527.5(LDLR):c.1301C>G (p.Thr434Arg)

dbSNP: rs745343524

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237295	SCV002817149	pathogenic	Hypercholesterolemia, familial, 1	2022-10-28	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1301C>G (p.Thr434Arg) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4, PM2, PM3, PP1_Strong, and PP4 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: PS4: Variant meets PM2 and is identified in 10 unrelated cases, as follows: 6 patients with DLCN >=6 and 2 patients with Simon-Broome criteria of possible FH from Centre de Genetique Moleculaire et Chromosomique, Unite de genetique de l'Obesite et des Dyslipidies; 1 case with MedPed criteria from PMID 21868016 (Garcia-Garcia et al., 2011); 1 case with DLCN>6 from PMID 10634824 (Deiana et al., 2000). So PS4 is met. PM2: This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PM3: Variant meets PM2 and is identified in 2 siblings from PMID 29306853 with childhood total cholesterol levels >700 mg/dL and homozygous for this variant. So PM3 is met. PP1_Strong: Variant segregates with FH phenotype in >1 families, as follows: 6 affected family members from Centre de Genetique Moleculaire et Chromosomique, Unite de genetique de l'Obesite et des Dyslipidies; 10 affected members tested positive and 7 unaffected members tested negative in one family in 17 informative meiosis from PMID 21868016, so PP1_Strong is met. PP4: Variant meets PM2 and is identified in 10 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details).
LDLR-LOVD, British Heart Foundation	RCV000237295	SCV000295353	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000237295	SCV000503330	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 7 , family members = 4 with unclear co-segregation in 1 family / FH-Sassari-4/Software predictions: Benign
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237295	SCV000583818	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Fundacion Hipercolesterolemia Familiar	RCV000237295	SCV000607584	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004767193	SCV005381406	pathogenic	Familial hypercholesterolemia	2024-08-05	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1301C>G (p.Thr434Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251382 control chromosomes. c.1301C>G has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Bertolini_2000, Fouchier_2001, Garcia-Garcia_2011, Garcia-Garcia_2001, Deina_2000, Albuquerque_2023) and observed to segregate with disease. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 37813054, 10978268, 10634824, 11810272, 21868016, 11668640). ClinVar contains an entry for this variant (Variation ID: 251774). Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237295	SCV000606388	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research