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.1187G>T (p.Gly396Val)

CA404084654

924165 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: b3b11700-6fc1-485c-8e28-de7abdf16f80

HGVS expressions

NM_000527.5:c.1187G>T

NM_000527.5(LDLR):c.1187G>T (p.Gly396Val)

NC_000019.10:g.11113278G>T

CM000681.2:g.11113278G>T

NC_000019.9:g.11223954G>T

CM000681.1:g.11223954G>T

NC_000019.8:g.11084954G>T

NG_009060.1:g.28898G>T

ENST00000558518.6:c.1187G>T

ENST00000252444.9:n.1441G>T

ENST00000455727.6:c.683G>T

ENST00000535915.5:c.1064G>T

ENST00000545707.5:c.806G>T

ENST00000557933.5:c.1187G>T

ENST00000558013.5:c.1187G>T

ENST00000558518.5:c.1187G>T

ENST00000560173.1:n.186G>T

ENST00000560467.1:n.667G>T

NM_000527.4:c.1187G>T

NM_001195798.1:c.1187G>T

NM_001195799.1:c.1064G>T

NM_001195800.1:c.683G>T

NM_001195803.1:c.806G>T

NM_001195798.2:c.1187G>T

NM_001195799.2:c.1064G>T

NM_001195800.2:c.683G>T

NM_001195803.2:c.806G>T

Uncertain Significance

PM2

PS3 PP3 PM5 BP4

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.1187G>T (p.Gly396Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code (PM2) 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). PP3/BP4 not met: REVEL=0.668, it is not above 0.75 but between 0.5-0.75, splicing evaluation required. Functional data on splicing is not available. In Scenario A, acceptor site: The variant is located at -20 to +3 bases of canonical acceptor splicing site of exon 9. Wild type canonical acceptor motif: CTCGCTCCCCGGACCCCCAGGCT, MES: 6.59; Variant canonical acceptor motif: CTCGCTCCCCGGACCCCCAGTCT, MES: 5.33. Var/Wt ratio = 0.81, which is greater than 0.8 and less than 1.0. Alternative splicing is not predicted. PS3 not met: Functional data not available. PP4, PS4 not met: Variant meets PM2, however clinical data is 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>A (p.Gly396Asp), (ClinVarID 440630), NM_000527.5 (LDLR):c.1186G>C (p.Gly396Arg), (ClinVarID 870321). 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).

PS3

Functional data not available.

PP3

REVEL=0.668, it is not above 0.75 but between 0.5-0.75, splicing evaluation required.

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>A (p.Gly396Asp), (ClinVarID 440630), NM_000527.5 (LDLR):c.1186G>C (p.Gly396Arg), (ClinVarID 870321). None is classified as Pathogenic by these guidelines, therefore PM5 is not met.

BP4

REVEL=0.668, it is not above 0.75 but between 0.5-0.75, splicing evaluation required. Functional data on splicing is not available. In Scenario A, acceptor site: The variant is located at -20 to +3 bases of canonical acceptor splicing site of exon 9. Wild type canonical acceptor motif: CTCGCTCCCCGGACCCCCAGGCT, MES: 6.59; Variant canonical acceptor motif: CTCGCTCCCCGGACCCCCAGTCT, MES: 5.33. Var/Wt ratio = 0.81, which is greater than 0.8 and less than 1.0. Alternative splicing is not predicted.

Approved on: 2022-10-28

Published on: 2022-12-24

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