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]

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

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA041918

251034 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

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

PP4 PM2 BS3

PS1 PS2 PS4 PS3 BP7 BP5 BP3 BP2 BP4 BP1 BA1 PP1 PP3 PP2 PVS1 PM5 PM4 PM3 PM1 PM6 BS2 BS4 BS1

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_000527.5(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.

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

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

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

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

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.

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

PVS1

Missense variant, PVS1 Not Met

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

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.

Curation History

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