Variant: NM_000527.5(LDLR):c.139G>A (p.Asp47Asn)

CA041918

251034 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 3942b390-0c9b-47c6-a385-abb5f16f9e7a

Approved on: 2021-06-07

Published on: 2021-06-24

HGVS expressions

NM_000527.5:c.139G>A
NM_000527.5(LDLR):c.139G>A (p.Asp47Asn)
ENST00000558518.6:c.139G>A
ENST00000252444.9:n.393G>A
ENST00000455727.6:c.139G>A
ENST00000535915.5:c.139G>A
ENST00000545707.5:c.139G>A
ENST00000557933.5:c.139G>A
ENST00000557958.1:n.225G>A
ENST00000558013.5:c.139G>A
ENST00000558518.5:c.139G>A
ENST00000560502.5:n.225G>A
NM_000527.4:c.139G>A
NM_001195798.1:c.139G>A
NM_001195799.1:c.139G>A
NM_001195800.1:c.139G>A
NM_001195803.1:c.139G>A
NM_001195798.2:c.139G>A
NM_001195799.2:c.139G>A
NM_001195800.2:c.139G>A
NM_001195803.2:c.139G>A
NC_000019.10:g.11100294G>A
CM000681.2:g.11100294G>A
NC_000019.9:g.11210970G>A
CM000681.1:g.11210970G>A
NC_000019.8:g.11071970G>A
NG_009060.1:g.15914G>A

Uncertain Significance

• Met criteria codes: PM2 BS3 PP4

• Not Met criteria codes: PM5 PM4 PM3 PM1 PM6 PVS1 BS2 BS4 BS1 BP7 BP5 BP3 BP2 BP4 BP1 PS1 PS2 PS4 PS3 PP1 PP3 PP2 BA1

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.139G>A (p.Asp47Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (BS3, PM2 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: BS3 - Level 1 assays: PMID 30413722: Heterologous cells (CHO-ldlA7), FACS and western blot assays - result - Normal (>90%) expression, binding and uptake ---- whole cycle is above 90% of wild-type activity, so BS3 is Met. PM2 - PopMax MAF = 0.0001307 (0.013%) in South Asian exomes (gnomAD v2.1.1). PP4 - Variant meets PM2. Identified in at least 1 FH case from Laboratory of Genetics and Molecular Cardiology who fulfill Simon-Broome criteria.

Met criteria codes

• PM2: gnomAD PopMax MAF = 0.0001307 (0.013%) in South Asian exomes (gnomAD v2.1.1).
• BS3: Level 1 assays: PMID 30413722: Heterologous cells (CHO-ldlA7), FACS and western blot assays - result - Normal (>90%) expression, binding and uptake ---- whole cycle is above 90% of wild-type activity, so BS3 is Met
• PP4: Variant meets PM2. Identified in at least 1 FH case from Laboratory of Genetics and Molecular Cardiology who fulfill Simon-Broome criteria (high LDL value, family history of high colesterol = possible FH) ---- PP4 is Met

Not Met criteria codes

• PM5: One more missense variant described in same codon: (1)NM_000527.4(LDLR):c.139G>C (p.Asp47His) (ClinVar ID 440546) - VUS by these guidelines --- variant is classified as VUS, so PM5 is Not Met.
• PM4: Missense variant, not applicable
• PM3: variant identified in 2 index cases from Laboratory of Genetics and Molecular Cardiology: - (#1) is compound heterozygote in trans with LDLR EX13-15DUP/FH Bologna 2 (ClinVar ID252077), Likely pathogenic by these guidelines, but with a phenotype that does not confirm or exclude homozygous FH, so BP2 is Not Met. - (#3) is compound heterozygote in trans with LDLR EX13-15DUP/FH Bologna 2 (ClinVar ID252077), Likely pathogenic by these guidelines, but with no phenotype information, so BP2 is Not Met.
• PM1: Missense at codon 47. PM2 is Met, but it is not exon 4 or any of the 60 Cys residues listed, so PM1 is Not Met
• PM6: no de novo cases were identified, so PM6 is Not Met
• PVS1: Missense variant, PVS1 Not Met
• BS2: no unaffected individuals identified with the variant, so BS2 is Not Met
• BS4: variant does not segregate with FH phenotype in 1 informative meiosis in 1 family from Laboratory of Genetics and Molecular Cardiology. not enough evidence to meet BS4 (only 1 family) ---- BS4 is Not Met
• BS1: FAF = 0.00004442 (0.004%) in south asian exomes (gnomAD v2.1.1). FAF is not under 0.2%, so BS1 is Not Met.
• BP7: Missense variant, so BP7 is not applicable
• BP5: Not applicable
• BP3: Not applicable
• BP2: variant identified in 2 index cases from Laboratory of Genetics and Molecular Cardiology: - (#1) is compound heterozygote in trans with LDLR EX13-15DUP/FH Bologna 2 (ClinVar ID252077), Likely pathogenic by these guidelines, but with a phenotype that does not confirm or exclude heterozygous FH, so BP2 is Not Met. - (#3) is compound heterozygote in trans with LDLR EX13-15DUP/FH Bologna 2 (ClinVar ID252077), Likely pathogenic by these guidelines, but with no phenotype information, so BP2 is Not Met.
• BP4: REVEL = 0.71. It is not below 0.15, so BP4 is Not Met
• BP1: Not applicable
• PS1: No variant described that leads to the same amino acid change, so PS1 is Not Met
• PS2: no de novo cases were identified, so PS2 is Not Met
• PS4: Variant meets PM2. Identified in at least 1 index case from Laboratory of Genetics and Molecular Cardiology who fulfills Simon-Broome criteria for FH. not enough evidence to meet PS4 ---- PS4 is Not Met
• PS3: Level 1 assays: PMID 30413722: Heterologous cells (CHO-ldlA7), FACS and western blot assays - result - Normal (>90%) expression, binding and uptake ---- results are not below 70% of wild-type activity, so PS3 is Not Met
• PP1: no segregations were identified. --- PP1 is Not Met
• PP3: REVEL = 0.71. It is not above 0.75, splicing evaluation required. Functional data on splicing not available. A) variant not on limits. B) variant is exonic and at least 50bp downstream from canonical acceptor site and 50 bp upstream of canonical donor, but it does not create GT or AG. C) there are no AG or GT nearby. No splicing prediction is applicable, so PP3 is Not Met
• PP2: Not applicable
• BA1: FAF = 0.00004442 (0.004%) in south asian exomes (gnomAD v2.1.1). FAF is not under 0.5%, so BA1 is Not Met.