Variant: NM_000527.5(LDLR):c.1359-1G>A

CA023463

162499 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 7df0b854-4c43-4327-b5a3-3421ff6c6a46

HGVS expressions

NM_000527.5:c.1359-1G>A
NM_000527.5(LDLR):c.1359-1G>A
NC_000019.10:g.11113534G>A
CM000681.2:g.11113534G>A
NC_000019.9:g.11224210G>A
CM000681.1:g.11224210G>A
NC_000019.8:g.11085210G>A
NG_009060.1:g.29154G>A
ENST00000558518.6:c.1359-1G>A
ENST00000252444.9:n.1613-1G>A
ENST00000455727.6:c.855-1G>A
ENST00000535915.5:c.1236-1G>A
ENST00000545707.5:c.978-1G>A
ENST00000557933.5:c.1359-1G>A
ENST00000558013.5:c.1359-1G>A
ENST00000558518.5:c.1359-1G>A
ENST00000559340.1:n.80-1G>A
ENST00000560467.1:n.839-1G>A
NM_000527.4:c.1359-1G>A
NM_001195798.1:c.1359-1G>A
NM_001195799.1:c.1236-1G>A
NM_001195800.1:c.855-1G>A
NM_001195803.1:c.978-1G>A
NR_106946.1:n.61G>A
NM_001195798.2:c.1359-1G>A
NM_001195799.2:c.1236-1G>A
NM_001195800.2:c.855-1G>A
NM_001195803.2:c.978-1G>A

Pathogenic

• Met criteria codes: PM2 PVS1 PP1_Strong PS3_Supporting PS4 PP4

• Not Met criteria codes: PM3 PM1 PM4 PM5 PM6 BA1 BS2 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PS2 PS1 PP3 PP2

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1359-1G>A variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1, PP1_Strong, PS4, PM2, PP4 and PS3_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 follows: PVS1 - variant is in canonical - 1 splice site and causes a frameshift in exon 10 (p.Thr454Leufs*51, from Holla et al., 2009 (PMID 19208450)), so PVS1 is met. PP1_strong - variant segregates with FH phenotype in 9 informative meiosis from at least 5 families: - 5 informative meiosis from 4 families from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière): 5 relatives with the variant have LDL-C >75th percentile. - 4 informative meiosis from at least 1 family from Mayo lab (Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory), Ambry lab (Ambry Genetics) and Arca lab (Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca), but are confirmed to be the same: 2 relatives with the variant had LDL >75th percentile and 2 relatives negative for variant had LDL <50th percentile. --- so PP1_Strong is met. PS4 - variant meets PM2 and was identified in: - 25 unrelated index cases (22 cases with DLCN >=6, 3 with possible Simon Broome FH from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France; - 2 unrelated index cases (MFH101: DLCN of 8, MFH116: meets MEDPED definite) reported by Mayo lab (Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory), Ambry lab (Ambry Genetics) and Arca lab (Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca), but are confirmed to be the same; - 1 index case with Dutch lipid clinic network >=6 from Robarts Research Institute, Canada; - 1 index case with DLCN >= 6 from Color Health, Inc., USA. --- 29 cases (no additional bibliographic search was done because number of index cases is already over 10), so PS4 is met. PM2 - PopMax MAF = 0.00002940 (0.003%) in European non-Finnish genomes (gnomAD v3.1.2). It is below 0.02%, so PM2 is met. PP4 - variant meets PM2 and was identified in at least 29 unrelated index cases (see PS4 for details), so PP4 is met. PS3_supporting - Level 2/3 FS: Holla et al., 2009 (PMID 19208450): Htz patients' Epstein Barr virus transformed lymphocytes, RNA assays - results: skipping of the first 7 nts from exon 10 in 23% of mRNAs (p.Thr454Leufs*51) --- aberrant transcript is confirmed by sequencing and is quantified, but it is not above 25% of total transcript, so PS3_Supporting is met.

Met criteria codes

• PM2: PopMax MAF = 0.00002940 (0.003%) in European non-Finnish genomes (gnomAD v3.1.2). It is below 0.02%, so PM2 is met
• PVS1: variant is in canonical - 1 splice site and causes a frameshift in exon 10 (p.Thr454Leufs*51, from Holla et al., 2009 (PMID 19208450)), so PVS1 is met
• PP1_Strong: variant segregates with FH phenotype in 9 informative meiosis from at least 5 families: - 5 informative meiosis from 4 families from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière): 5 relatives with the variant have LDL-C >75th percentile. - 4 informative meiosis from at least 1 family from Mayo lab (Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory), Ambry lab (Ambry Genetics) and Arca lab (Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca), but are confirmed to be the same: 2 relatives with the variant had LDL >75th percentile and 2 relatives negative for variant had LDL <50th percentile. so PP1_Strong is met
• PS3_Supporting: Level 2/3 FS: Holla et al., 2009 (PMID 19208450): Htz patients' Epstein Barr virus transformed lymphocytes, RNA assays - results: skipping of the first 7 nts from exon 10 in 23% of mRNAs (p.Thr454Leufs*51) --- aberrant transcript is confirmed by sequencing and is quantified, but it is not above 25% of total transcript, so PS3_Supporting is met
• PS4: variant meets PM2 and was identified in: - 25 unrelated index cases (22 cases with DLCN >=6, 3 with possible Simon Broome FH from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France; - 2 unrelated index cases (MFH101: DLCN of 8, MFH116: meets MEDPED definite) reported by Mayo lab (Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory), Ambry lab (Ambry Genetics) and Arca lab (Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca), but are confirmed to be the same; - 1 index case with Dutch lipid clinic network >=6 from Robarts Research Institute, Canada; - 1 index case with DLCN >= 6 from Color Health, Inc., USA. --- 29 cases (no additional bibliographic search was done because number of index cases is already over 10), so PS4 is met
• PP4: variant meets PM2 and was identified in: - 25 unrelated index cases (22 cases with DLCN >=6, 3 with possible Simon Broome FH from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France; - 2 unrelated index cases (MFH101: DLCN of 8, MFH116: meets MEDPED definite) reported by Mayo lab (Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory), Ambry lab (Ambry Genetics) and Arca lab (Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca), but are confirmed to be the same; - 1 index case with Dutch lipid clinic network >=6 from Robarts Research Institute, Canada; - 1 index case with DLCN >= 6 from Color Health, Inc., USA. --- 29 cases (no additional bibliographic search was done because number of index cases is already over 10), so PP4 is met

Not Met criteria codes

• PM3: variant meets PM2 and was identified in 1 index case who is also heterozygous for NM_000527.5(LDLR):c.1775G>A (p.Gly592Glu) (phase unknown) from Ambry Genetics. --- 2nd variant is classified as Pathogenic by these guidelines, but phase is unknown and there is not LDL values, so PM3 is not met
• PM1: variant is intronic, so not met
• PM4: variant is intronic, so not met
• PM5: variant is intronic, so not met
• PM6: no de novo occurrence
• BA1: FAF = 0.000004880 (0.0005%) in European non-Finnish genomes (gnomAD v3.1.2). It is not above 0.5%, so not met
• BS2: not identified in normolipidemic individuals: 0/1000 normolipidemic individuals from Robarts Research Institute, so not met
• BS4: no evidence of lack of segregation, so not met
• BS3: Level 3 FS: Holla et al., 2009 (PMID 19208450): Htz patients' Epstein Barr virus transformed lymphocytes, RNA assays - results: skipping of the first 7 nts from exon 10 in 23% of mRNAs (p.Thr454Leufs*51) --- functional study is consistent with damaging effect, so not met
• BS1: FAF = 0.000004880 (0.0005%) in European non-Finnish genomes (gnomAD v3.1.2). It is not above 0.2%, so not met
• BP2: variant meets PM2 and was identified in 1 index case who is also heterozygous for NM_000527.5(LDLR):c.1775G>A (p.Gly592Glu) (phase unknown) from Ambry Genetics. --- 2nd variant is classified as Pathogenic by these guidelines, but phase is unknown and there is not LDL values, so BP2 is not met
• BP3: not applicable
• BP4: Variant meets PVS1, so not met
• BP1: not applicable
• BP5: not applicable
• BP7: variant is intronic, so not met
• PS2: no de novo occurrence
• PS1: variant is intronic, so not met
• PP3: Variant meets PVS1, so not met
• PP2: not applicable

Approved on: 2022-08-28

Published on: 2022-08-28