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.1598G>A (p.Trp533Ter)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA035378

251926 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: bf9aaff6-ebfa-43dd-8599-f96ac01722f1

Approved on: 2022-08-28

Published on: 2022-08-28

HGVS expressions

NM_000527.5:c.1598G>A

NM_000527.5(LDLR):c.1598G>A (p.Trp533Ter)

NC_000019.10:g.11116105G>A

CM000681.2:g.11116105G>A

NC_000019.9:g.11226781G>A

CM000681.1:g.11226781G>A

NC_000019.8:g.11087781G>A

NG_009060.1:g.31725G>A

ENST00000558518.6:c.1598G>A

ENST00000252444.9:n.1852G>A

ENST00000455727.6:c.1094G>A

ENST00000535915.5:c.1475G>A

ENST00000545707.5:c.1217G>A

ENST00000557933.5:c.1598G>A

ENST00000558013.5:c.1598G>A

ENST00000558518.5:c.1598G>A

ENST00000559340.1:n.319G>A

NM_000527.4:c.1598G>A

NM_001195798.1:c.1598G>A

NM_001195799.1:c.1475G>A

NM_001195800.1:c.1094G>A

NM_001195803.1:c.1217G>A

NM_001195798.2:c.1598G>A

NM_001195799.2:c.1475G>A

NM_001195800.2:c.1094G>A

NM_001195803.2:c.1217G>A

Pathogenic

PVS1 PS4_Supporting PP4 PM2

BS4 BS3 BS1 BS2 BP5 BP7 BP2 BP3 PS2 PS3 PS1 BA1 PP1 PM6 PM3 PM1 PM4 PM5

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.1

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1598G>A (p.Trp533Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1, PM2, PP4 and PS4_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 nonsense upstream of amino acid 830, so PVS1 is met. PM2 - PopMax MAF = 0.000008792 (0.0009%) in European Non-Finnish exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met. PP4 - variant meets PM2. identified in: - 1 index case who fulfills SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge. - 1 index case who fulfills SB criteria from Marduel et al. 2010 (PMID: 20809525). so PP4 is met. PS4_supporting - variant meets PM2 and was identified in 2 unrelated index cases from different labs (please see PP4 for details), so PS4_Supporitng is met.

PVS1

variant is nonsense upstream of amino acid 830, so PVS1 is met

PS4_Supporting

variant meets PM2. identified in: - 1 index case who fulfills SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge. - 1 index case who fulfills SB criteria from Marduel et al. 2010 (PMID: 20809525). so PS4_Supporting is met

PP4

PM2

PopMax MAF = 0.000008792 (0.0009%) in European Non-Finnish exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met

BS4

no evidence of lack of segregation

BS3

there are no functional studies

BS1

no FAF, just total MAF = 0.000003977 (0.0004%) in European Non-Finnish exomes (gnomAD v2.1.1). so BS1 is not met

BS2

not identified in normolipidemic individuals: 0/190 non-FH alleles from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, so BS2 is not met

BP5

not applicable

BP7

variant is nonsense, so not applicable

BP2

index case from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge with LDL = 258mg/dl also has NM_000527.5(LDLR):c.1875C>T (p.Asn625=) - Likely benign by these guidelines. Also, there is no certainty if the 2 variants are in trans, so BP2 is not met

BP3

not applicable

PS2

no de novo occurrence

PS3

there are no functional studies

PS1

variant is nonsense, so not applicable

BA1

no FAF, just total MAF = 0.000003977 (0.0004%) in European Non-Finnish exomes (gnomAD v2.1.1). so BA1 is not met

PP1

Variant segregates with FH phenotype in 1 informative meiosis from 1 family from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge: 1 relative has the phenotype and the variant. not enough, so not met

PM6

no de novo occurrence

PM3

no index case with homozygous phenotype

PM1

variant is nonsense, so not applicable

PM4

variant is nonsense, so not applicable

PM5

variant is nonsense, so not applicable

Curation History

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