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]

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Variant: NM_000527.5(LDLR):c.1359-5C>G

CA10585422

251808 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 73216f9d-b472-44cf-a82f-136037e4541b

HGVS expressions

NM_000527.5:c.1359-5C>G

NM_000527.5(LDLR):c.1359-5C>G

NC_000019.10:g.11113530C>G

CM000681.2:g.11113530C>G

NC_000019.9:g.11224206C>G

CM000681.1:g.11224206C>G

NC_000019.8:g.11085206C>G

NG_009060.1:g.29150C>G

ENST00000558518.6:c.1359-5C>G

ENST00000252444.9:n.1613-5C>G

ENST00000455727.6:c.855-5C>G

ENST00000535915.5:c.1236-5C>G

ENST00000545707.5:c.978-5C>G

ENST00000557933.5:c.1359-5C>G

ENST00000558013.5:c.1359-5C>G

ENST00000558518.5:c.1359-5C>G

ENST00000559340.1:n.80-5C>G

ENST00000560467.1:n.839-5C>G

NM_000527.4:c.1359-5C>G

NM_001195798.1:c.1359-5C>G

NM_001195799.1:c.1236-5C>G

NM_001195800.1:c.855-5C>G

NM_001195803.1:c.978-5C>G

NR_106946.1:n.57C>G

NM_001195798.2:c.1359-5C>G

NM_001195799.2:c.1236-5C>G

NM_001195800.2:c.855-5C>G

NM_001195803.2:c.978-5C>G

Likely Pathogenic

PP4 PM2 PP1_Moderate PS4_Supporting PS3_Supporting

PP3 BS4

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.1359-5C>G variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_moderate, PM2, PP4, PS3_supporting, 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: PP1_moderate: Variant segregates with FH phenotype in 4 informative meioses in 1 family from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge PM2: PopMax MAF = 0.00001766 (0.001766%) in European (non-Finnish) population exomes (gnomAD v2.1.1). PP3: No REVEL, splicing evaluation required. Functional data on splicing not available. A) variant located at -20 to +3 bases from canonical acceptor splice site, MES scores: canonical site variant = 4.09; canonical acceptor wt = 6.76. Ratio variant/wt canonical acceptor: 4.09/6.76 = 0.605 ---- It is below 0.8 Variant is predicted to alter splicing. PP4: Variant meets PM2 and is identified in at least 3 index cases (1 index from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge who meets the Simon Broome Possible criteria; 1 case with Simon-Broome criteria of possible FH in PMID: 19411563, and 1 case with Simon-Broome criteria of possible FH in PMID: 30876530), after alternative causes of high cholesterol were excluded PS3_supporting: Level 3 assay: PMID 19411563: Heterozygous patients' lymphocytes, RNA assays - result - Retention of intron 9 (p.Ser453Argfs*2) ---- functional study is consistent with damaging effect. PS4_supporting: Variant meets PM2 and is identified in 3 index cases (1 index from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge who meets the Simon Broome Possible criteria; 1 case with Simon-Broome criteria of possible FH in PMID: 19411563, and 1 case with Simon-Broome criteria of possible FH in PMID: 30876530).

PP4

Variant meets PM2 and is identified in at least 3 index cases (1 index from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge who meets the Simon Broome Possible criteria; 1 case with Simon-Broome criteria of possible FH in PMID: 19411563, and 1 case with Simon-Broome criteria of possible FH in PMID: 30876530), after alternative causes of high cholesterol were excluded

PM2

PopMax MAF = 0.00001766 (0.001766%) in European (non-Finnish) population exomes (gnomAD v2.1.1).

PP1_Moderate

Variant segregates with FH phenotype in 4 informative meioses in 1 family from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge

PS4_Supporting

Variant meets PM2 and is identified in 3 index cases (1 index from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge who meets the Simon Broome Possible criteria; 1 case with Simon-Broome criteria of possible FH in PMID: 19411563, and 1 case with Simon-Broome criteria of possible FH in PMID: 30876530).

PS3_Supporting

Level 3 assay: PMID 19411563: Heterozygous patients' lymphocytes, RNA assays - result - Retention of intron 9 (p.Ser453Argfs*2) ---- functional study is consistent with damaging effect.

PP3

PP3 not MET when functional data available.

BS4

Lack of segregation from 1 family in data from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge, with 2 informative meioses. In PMID: 19411563, 1 non-segregation (informative meiosis) in 1 family, so did not count this family. For BS4 to apply, data must be available on larger than 2 informative meiosis in each family. So BS4 not MET.

Approved on: 2022-08-27

Published on: 2022-12-23

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