Submissions for variant NM_000527.5(LDLR):c.1954A>G (p.Met652Val)

gnomAD frequency: 0.00003  dbSNP: rs730882111

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237649	SCV002817177	uncertain significance	Hypercholesterolemia, familial, 1	2022-12-23	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1954A>G (p.Met652Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and BS3_Supporting 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 follow: PM2_Met : Allele frequency is 0.00002 in European (Non-Finnish) subpopulation (>129178 alleles tested) in GnomAD (gnomAD v2.1.1).
LDLR-LOVD, British Heart Foundation	RCV000237649	SCV000295773	likely benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330519	SCV004039145	uncertain significance	not specified	2023-08-14	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1954A>G (p.Met652Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251460 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1954A>G has been reported in the literature in at least two individuals affected with high cholesterol (Balder_2018, Leren_2021). However, these report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. c.1954A>G has also been identified in at least two control individuals who did not have a history of myocardial infarction (Do_2015, Thormaehlen_2018), however cholesterol levels for these individuals were not provided. At least one functional study investigating protein overexpression and complementation showed no damaging effect of this variant (Thormaehlen_2018). The following publications have been ascertained in the context of this evaluation (PMID: 29459468, 25487149, 33740630, 25647241). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely benign, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000162006	SCV000189581	not provided	not provided		no assertion provided	in vitro
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237649	SCV000606562	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research