Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_000527.4(LDLR):c.313+1G>A

CA023688

3736 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 1f8ff66d-e0d4-47ed-af0f-b63b943b5e33

HGVS expressions

NM_000527.4:c.313+1G>A

NM_000527.4(LDLR):c.313+1G>A

ENST00000558518.6:c.313+1G>A

ENST00000252444.9:n.567+1G>A

ENST00000455727.6:c.313+1G>A

ENST00000535915.5:c.191-2433G>A

ENST00000545707.5:c.313+1G>A

ENST00000557933.5:c.313+1G>A

ENST00000557958.1:n.400G>A

ENST00000558013.5:c.313+1G>A

ENST00000558518.5:c.313+1G>A

NM_001195798.1:c.313+1G>A

NM_001195799.1:c.191-2433G>A

NM_001195800.1:c.313+1G>A

NM_001195803.1:c.313+1G>A

NM_000527.5:c.313+1G>A

NM_001195798.2:c.313+1G>A

NM_001195799.2:c.191-2433G>A

NM_001195800.2:c.313+1G>A

NM_001195803.2:c.313+1G>A

NC_000019.10:g.11102787G>A

CM000681.2:g.11102787G>A

NC_000019.9:g.11213463G>A

CM000681.1:g.11213463G>A

NC_000019.8:g.11074463G>A

NG_009060.1:g.18407G>A

Pathogenic

PP1_Strong PS3_Moderate PS4 PP4 PVS1_Strong PM2

PS2 PS1 PP3 PP2 BA1 PM6 BS3 BS1 BS4 PM3 PM4 PM1 PM5 BS2 BP7 BP5 BP4 BP1 BP2 BP3

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.4(LDLR):c.313+1G>A variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1_Strong, PS4, PP1_Strong, PM2, PS3_Moderate and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PVS1_strong - Variant is in canonical GT +1 splice site, predicted to lead to exon 3 skipping (in frame). PS4 - Variant meets PM2. Identified in at least 14 unrelated index cases from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with DLCS equal or above 6. PP1_strong - variant segregates with FH phenotype in 6 informative meiosis in 5 families from different laboratories. PM2 - PopMax MAF = 0.00006156 (0.006%) in European non-Finnish exomes (gnomAD v2.1.1). PS3_moderate Level 2 assays: PMID 19361455: Hmz patients' Epstein-Barr tranformed lymphocytes, RNA and FACS assays - results - Alternative splicing: skipping of exon 3 or inclusion of intron 3; amount of cell-surface LDLR 33% of normal (Hmz); 12% LDL-LDLR uptake in Hmz ---- Aberrant transcripts confirmed by sequencing and above 25% of total transcript, and uptake is below 70% of wild-type, so PS3_moderate is Met. PP4 - Variant meets PM2. Identified in 3 FH cases from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge who fulfill Simon-Broome criteria and in 13 FH cases from University of British Columbia (UBC, Canada) and 14 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with clinical Dutch Lipid Clinic Network Criteria score ≥ 6.

PP1_Strong

variant segregates with FH phenotype in 6 informative meiosis in 5 families from different laboratories (University of British Columbia and Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge): 5 affected family members have the variant and 1 non-affected family member does not have the variant. --- PP1_Strong is Met

PS3_Moderate

Level 2 assays: PMID 19361455: Hmz patients' Epstein-Barr tranformed lymphocytes, RNA and FACS assays - results - Alternative splicing: skipping of exon 3 or inclusion of intron 3 (p.Pro105_Ala860delinsArgLysCysGlyProAlaPheAlaIleGluProIle); amount of cell-surface LDLR 33% of normal (Hmz); 12% LDL-LDLR uptake in Hmz ---- Aberrant transcripts confirmed by sequencing and above 25% of total transcript, and uptake is below 70% of wild-type, so PS3_moderate is Met / Level 2 assays: PMID 19148831: Epstein-Barr virus (EBV) transformed lymphocytes from Hmz patients, FACS, WB and RNA assays - results - amount of protein 10% of wild-type, 10% uptake, amount of transcripts 60-70% of wild-type ---- Uptake and amount of protein are below 70% of wild-type, so PS3_moderate is Met / Level 3 assays: PMID 8829662: Hmz patients' lymphocytes, RNA assays - results - skipping of exon 3 (p.Leu64_Pro105delinsSer) ---- Aberrant transcripts confirmed by sequencing, so PS3_supporting would be Met, but PS3_moderate is already Met

PS4

Variant meets PM2. Identified in at least 14 unrelated index cases from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with DLCS equal or above 6. ---- PS4 is Met

PP4

Variant meets PM2. Identified in 3 FH cases from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge who fulfill Simon-Broome criteria and in 13 FH cases from University of British Columbia (UBC, Canada) and 14 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with clinical Dutch Lipid Clinic Network Criteria score ≥ 6. ---- PP4 is Met

PVS1_Strong

Variant is in canonical GT +1 splice site, predicted to lead to exon 3 skipping (in frame), so PVS1_Strong is Met

PM2

PopMax MAF = 0.00006156 (0.006%) in European non-Finnish exomes (gnomAD v2.1.1).

PS2

no de novo cases were identified, so PS2 is Not Met

PS1

Intronic variant, PS1 not applicable

PP3

PVS1_Strong is Met, so PP3 is not applicable

PP2

Not applicable

BA1

FAF = 0.00002854 (0.003%) in european non-finnish exomes (gnomAD v2.1.1). FAF is not above 0.5%, so BA1 is Not Met.

PM6

no de novo cases were identified, so PM6 is Not Met

BS3

Level 3(benign) assays: PMID 19361455: Hmz patients' Epstein-Barr tranformed lymphocytes, RNA and FACS assays - results - Alternative splicing: skipping of exon 3 or inclusion of intron 3 (p.Pro105_Ala860delinsArgLysCysGlyProAlaPheAlaIleGluProIle); amount of cell-surface LDLR 33% of normal (Hmz); 12% LDL-LDLR uptake in Hmz ---- Aberrant transcripts confirmed by sequencing and whole cycle not above 90% of wild-type, BS3_supportig is Not Met / Level 3(benign) assays: PMID 19148831: Epstein-Barr virus (EBV) transformed lymphocytes from Hmz patients, FACS, WB and RNA assays - results - amount of protein 10% of wild-type, 10% uptake, amount of transcripts 60-70% of wild-type ---- Whole cycle not above 90% of wild-type, BS3_supporting is Not Met / Level 3(benign) assays: PMID 8829662: Hmz patients' lymphocytes, RNA assays - results - skipping of exon 3 (p.Leu64_Pro105delinsSer) ---- Aberrant transcripts confirmed by sequencing, so BS3_supporting is Not Met

BS1

FAF = 0.00002854 (0.003%) in european non-finnish exomes (gnomAD v2.1.1). FAF is not above 0.2%, so BS1 is Not Met.

BS4

no non-segregations were identified, so BS4 is Not Met

PM3

not identified in individuals with other variants, so PM3 is Not Met

PM4

Intronic variant (predicted to cause in frame skipping of 1 whole exon - in PM4 is only considered indels smaller than whole exon to avoid double counting with PVS1), so PM4 is Not Met

PM1

Intronic variant, so PM1 is Not applicable

PM5

Intronic variant, PM5 not applicable

BS2

no unaffected individuals identified with the variant, so BS2 is Not Met

BP7

Intronic variant, so BP7 is not applicable

BP5

Not applicable

BP4

PVS1_Strong is Met, so BP4 is not applicable

BP1

Not applicable

BP2

not identified in individuals with other variants, so BP2 is Not Met

BP3

Not applicable

Approved on: 2021-06-07

Published on: 2021-06-24

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