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.1186G>C (p.Gly396Arg)

CA404083996

870321 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: c6d40a01-0c3b-4989-8b0c-1a8ff638b450

HGVS expressions

NM_000527.5:c.1186G>C

NM_000527.5(LDLR):c.1186G>C (p.Gly396Arg)

NC_000019.10:g.11111639G>C

CM000681.2:g.11111639G>C

NC_000019.9:g.11222315G>C

CM000681.1:g.11222315G>C

NC_000019.8:g.11083315G>C

NG_009060.1:g.27259G>C

ENST00000558518.6:c.1186G>C

ENST00000252444.9:n.1440G>C

ENST00000455727.6:c.682G>C

ENST00000535915.5:c.1063G>C

ENST00000545707.5:c.805G>C

ENST00000557933.5:c.1186G>C

ENST00000558013.5:c.1186G>C

ENST00000558518.5:c.1186G>C

ENST00000560173.1:n.185G>C

ENST00000560467.1:n.666G>C

NM_000527.4:c.1186G>C

NM_001195798.1:c.1186G>C

NM_001195799.1:c.1063G>C

NM_001195800.1:c.682G>C

NM_001195803.1:c.805G>C

NM_001195798.2:c.1186G>C

NM_001195799.2:c.1063G>C

NM_001195800.2:c.682G>C

NM_001195803.2:c.805G>C

Uncertain Significance

PM2 PP4 PP3

PM5 PS3

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.1186G>C (p.Gly396Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4) 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: PM2: This variant is absent from gnomAD (gnomAD version 2.1.1). PP4: Variant meets PM2 and is identified in 1 index case who fulfil Simon Broome criteria for definite/possible FH after alternative causes of high cholesterol were excluded. Reported by Miroshnikova et al, National Research Center ”Kurchatov Institute”, Gatchina, Russian Federation, PMID 33269076. PP3: REVEL= 0.702, it is not above 0.75, splicing evaluation required. Functional data on splicing is not available. The variant is predicted affecting splicing process in scenario A, donor site: The variant is located at -3 to +6 bases of canonical donor splicing site of exon 8. Wild type canonical donor motif: TGGGTGAGC, MES: 7.23 Variant canonical donor motif: TGCGTGAGC, MES: 3.45. Var/Wt ratio = 0.48, (< 0.8), met PP3. PS3 not met: Functional data not available. PM5 not met: Three other missense variants in the same codon: NM_000527.5 (LDLR):c.1186G>A (p.Gly396Ser), (ClinVarID 251704), NM_000527.5 (LDLR):c.1187G>T (p.Gly396Val), (ClinVarID 924165), NM_000527.5 (LDLR):c.1187G>A (p.Gly396Asp), (ClinVarID 440630). None is classified as Pathogenic by these guidelines, therefore PM5 is not met.

PM2

This variant is absent from gnomAD (gnomAD version 2.1.1).

PP4

Variant meets PM2 and is identified in 1 index case who fulfil Simon Broome criteria for definite/possible FH after alternative causes of high cholesterol were excluded. Reported by Miroshnikova et al, National Research Center ”Kurchatov Institute”, Gatchina, Russian Federation, PMID 33269076.

PP3

REVEL= 0.702, it is not above 0.75, splicing evaluation required. Functional data on splicing is not available. The variant is predicted affecting splicing process in scenario A, donor site: The variant is located at -3 to +6 bases of canonical donor splicing site of exon 8. Wild type canonical donor motif: TGGGTGAGC, MES: 7.23 Variant canonical donor motif: TGCGTGAGC, MES: 3.45. Var/Wt ratio = 0.48, (< 0.8), met PP3.

PM5

Three other missense variants in the same codon: NM_000527.5 (LDLR):c.1186G>A (p.Gly396Ser), (ClinVarID 251704), NM_000527.5 (LDLR):c.1187G>T (p.Gly396Val), (ClinVarID 924165), NM_000527.5 (LDLR):c.1187G>A (p.Gly396Asp), (ClinVarID 440630). None is classified as Pathogenic by these guidelines, therefore PM5 is not met.

PS3

Functional data not available.

Approved on: 2022-10-28

Published on: 2022-12-24

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