Variant: NM_000527.5(LDLR):c.344G>A (p.Arg115His)

CA043240

225402 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 42638e60-83a0-44a9-aefb-814182bee33a

HGVS expressions

NM_000527.5:c.344G>A
NM_000527.5(LDLR):c.344G>A (p.Arg115His)
ENST00000558518.6:c.344G>A
ENST00000252444.9:n.598G>A
ENST00000455727.6:c.314-2142G>A
ENST00000535915.5:c.221G>A
ENST00000545707.5:c.314-1315G>A
ENST00000557933.5:c.344G>A
ENST00000558013.5:c.344G>A
ENST00000558518.5:c.344G>A
NM_000527.4:c.344G>A
NM_001195798.1:c.344G>A
NM_001195799.1:c.221G>A
NM_001195800.1:c.314-2142G>A
NM_001195803.1:c.314-1315G>A
NM_001195798.2:c.344G>A
NM_001195799.2:c.221G>A
NM_001195800.2:c.314-2142G>A
NM_001195803.2:c.314-1315G>A
NC_000019.10:g.11105250G>A
CM000681.2:g.11105250G>A
NC_000019.9:g.11215926G>A
CM000681.1:g.11215926G>A
NC_000019.8:g.11076926G>A
NG_009060.1:g.20870G>A

Uncertain Significance

• Met criteria codes: PS3

• Not Met criteria codes: PVS1 PS2 PS4 PS1 PP4 PP3 PP2 PP1 PM6 PM2 PM3 PM4 PM1 PM5 BA1 BS2 BS4 BS1 BS3 BP5 BP7 BP4 BP1 BP2 BP3

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.344G>A (p.Arg115His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PS3) 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: PS3 - Level 1 assays: PMID 12837857: Heterologous cells (COS-7), FACS assays - results - 64% LDLR expression and activity ---- results are below 70% of wild-type, so PS3 is Met.

Met criteria codes

• PS3: Level 1 assays: PMID 12837857: Heterologous cells (COS-7), FACS assays - results - 64% LDLR expression and activity ---- results are below 70% of wild-type, so PS3 is Met (PMID 29874871 only refers to PMID 12837857 results)

Not Met criteria codes

• PVS1: Missense variant, PVS1 Not Met
• PS2: no de novo cases were identified, so PS2 is Not Met
• PS4: variant does not meet PM2, so PS4 is Not Met
• PS1: No variant described that leads to the same amino acid change, so PS1 is Not Met
• PP4: Variant does not meet PM2, so PP4 is Not Met
• PP3: REVEL = 0.684. It is not above 0.75, splicing evaluation is required. Functional data on splicing not available. A) variant not on limits. B) variant is exonic and at least 50bp upstream of canonical donor, but it does not create AG. C) there is AG nearby: MES scores: variant cryptic = -2.67, wt cryptic = -3.23, canonical acceptor = 8.16. scores are negative, which means they are not used, so PP3 is Not Met
• PP2: Not applicable
• PP1: no family members were tested, so PP1 is Not Met
• PM6: no de novo cases were identified, so PM6 is Not Met
• PM2: PopMax MAF = 0.002260 (0.23%) in East Asian exomes (gnomAD v2.1.1). MAF is not under 0.02%, so PM2 is Not Met
• PM3: not identified in individuals with other variants, so PM3 is Not Met
• PM4: Missense variant, not applicable
• PM1: Missense at codon 115. PM2 is Not Met, so even though it is exon 4, PM1 is Not Met
• PM5: One more missense variant described in same codon: (1)NM_000527.5(LDLR):c.344G>A (p.Arg115His) (ClinVar ID 225402) - classified as VUS by these guidelines, so PM5 is Not Met
• BA1: FAF = 0.001691 (0.169%) in East Asian exomes (gnomAD v2.1.1). FAF is not above 0.5%, so BA1 is Not Met.
• BS2: no unaffected individuals identified with the variant, so BS2 is Not Met
• BS4: no family members were tested, so BS4 is Not Met
• BS1: FAF = 0.001691 (0.169%) in East Asian exomes (gnomAD v2.1.1). FAF is not above 0.2%, so BS1 is Not Met
• BS3: Level 1 assays: PMID 12837857: Heterologous cells (COS-7), FACS assays - results - 64% LDLR expression and activity ---- whole cycle is not above 90% of wild-type, so BS3 is Not Met (PMID 29874871 only refers to PMID 12837857 results)
• BP5: Not applicable
• BP7: Missense variant, so BP7 is not applicable
• BP4: REVEL = 0.684. It is not below 0.15, so BP4 is Not Met
• 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