ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1A>C (p.Met1Leu)

dbSNP: rs879254382
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000237553 SCV002506383 pathogenic Hypercholesterolemia, familial, 1 2022-04-22 reviewed by expert panel curation The NM_000527.5(LDLR):c.1A>C (p.Met1Leu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes as PM2, PVS1_Moderate, PS3, PS4_Supporting, PP1_Moderate, 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: PM2 - variant is absent from gnomAD (v2.1.1). PVS1_Moderate – variant is predicted to affect the initiation codon. PS3 - Level 1 functional studies performed - Heterologous cells (CHO), FACS: results of 60% cell surface LDLR, 59% LDL binding and 66% LDL uptake, compared to wild-type. Note - Level 3 luciferase reporter assays were also performed: results of 5% luciferase construct activity compared to wild-type. Both studies performed in PMID: 34572405. PS4_Supporting - variant meets PM2 and is identified in 4 unrelated index cases who fulfill clinical criteria for FH (4 cases with SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – FH VCEP member lab). PP1_Moderate – variant segregates with phenotype in 4 informative meioses in 3 families (Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – 3 families: 4 affected relatives with the variant). PP4 - variant meets PM2 and is identified in >1 case who met clinical criteria for FH after alternative causes for high cholesterol were excluded. Note: four other missense variants at this same codon have been reported: 1) NM_000527.5(LDLR):c.1A>G (p.Met1Val) – Likely pathogenic by these guidelines. 2) NM_000527.4(LDLR):c.2T>C (p.Met1Thr) - Likely pathogenic by these guidelines. 3) NM_000527.4(LDLR):c.3G>A (p.Met1Ile) - Likely pathogenic by these guidelines. 4) NM_000527.5(LDLR):c.3G>T (p.Met1Ile) - Likely pathogenic by these guidelines. -PM5 not applicable as such variants must be Pathogenic.
LDLR-LOVD, British Heart Foundation RCV000237553 SCV000294405 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237553 SCV000322871 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research 0/190 non-FH alleles; 0/200 normal chromosomes
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237553 SCV000605990 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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