Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
Link to SEPIO compliant JSON-LD document

Variant: NM_000527.5(LDLR):c.642G>A (p.Trp214Ter)

CA10585029

251340 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: ecdf9c5f-f262-4f76-aee8-d7a7e435de78

HGVS expressions

NM_000527.5:c.642G>A
NM_000527.5(LDLR):c.642G>A (p.Trp214Ter)
NC_000019.10:g.11105548G>A
CM000681.2:g.11105548G>A
NC_000019.9:g.11216224G>A
CM000681.1:g.11216224G>A
NC_000019.8:g.11077224G>A
NG_009060.1:g.21168G>A
ENST00000558518.6:c.642G>A
ENST00000252444.9:n.896G>A
ENST00000455727.6:c.314-1844G>A
ENST00000535915.5:c.519G>A
ENST00000545707.5:c.314-1017G>A
ENST00000557933.5:c.642G>A
ENST00000558013.5:c.642G>A
ENST00000558518.5:c.642G>A
ENST00000560467.1:n.242G>A
NM_000527.4:c.642G>A
NM_001195798.1:c.642G>A
NM_001195799.1:c.519G>A
NM_001195800.1:c.314-1844G>A
NM_001195803.1:c.314-1017G>A
NM_001195798.2:c.642G>A
NM_001195799.2:c.519G>A
NM_001195800.2:c.314-1844G>A
NM_001195803.2:c.314-1017G>A

Pathogenic

Met criteria codes 3
PM2 PVS1 PP4
Not Met criteria codes 23
PS2 PS4 PS3 PS1 PM3 PM1 PM4 PM5 PM6 BA1 BP5 BP7 BP2 BP3 BP4 BP1 BS4 BS3 BS1 BS2 PP1 PP3 PP2

Evidence Links 0

Expert Panel

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.642G>A (p.Trp214Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PM2 and 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: PVS1 - variant is nonsense in exon 4 (amino terminal of amino acid 830), so PVS1 is met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PP4 - variant meets PM2 and was identified in at least 1 index case with SB criteria of definite FH (A+B) (Diagnostic criteria for heterozygous FH used in the paper were a TC>8.0 mmol/l and LDL- C>6.0 mmol/l if available, tendon xanthomata in the patient or in a first-degree relative, and a family history of hypercholesterolemia) from PMID 10532689 (Jensen et al., 1999), Denmark. so PP4 is met.
Met criteria codes
PM2
This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met
PVS1
variant is nonsense in exon 4 (amino terminal of amino acid 830), so PVS1 is met
PP4
variant meets PM2 and was identified in: - at least 1 index case with SB criteria of definite FH (A+B) (Diagnostic criteria for heterozygous FH used in the paper were a TC>8.0 mmol/l and LDL- C>6.0 mmol/l if available, tendon xanthomata in the patient or in a first-degree relative, and a family history of hypercholesterolemia) from PMID 10532689 (Jensen et al., 1999), Denmark. so PP4 is met
Not Met criteria codes
PS2
no de novo occurrence identified
PS4
variant meets PM2 and was identified in: - at least 1 index case with SB criteria of definite FH (A+B) (Diagnostic criteria for heterozygous FH used in the paper were a TC>8.0 mmol/l and LDL- C>6.0 mmol/l if available, tendon xanthomata in the patient or in a first-degree relative, and a family history of hypercholesterolemia) from PMID 10532689 (Jensen et al., 1999), Denmark. not enough for PS4, so not met
PS3
variant was not studied in functional study
PS1
variant is nonsense, so not applicable
PM3
no other variants identified in index cases
PM1
variant is nonsense, so not applicable
PM4
variant is nonsense, so not applicable
PM5
variant is nonsense, so not applicable
PM6
no de novo occurrence identified
BA1
This variant is absent from gnomAD (gnomAD v2.1.1).
BP5
not applicable
BP7
variant is nonsense, so not applicable
BP2
no other variants identified in index cases
BP3
not applicable
BP4
variant meets PVS1, so not met
BP1
not applicable
BS4
no segregation data
BS3
variant was not studied in functional study
BS1
This variant is absent from gnomAD (gnomAD v2.1.1).
BS2
variant was not searched in normolipidemic individuals
PP1
no segregation data
PP3
variant meets PVS1, so not met
PP2
not applicable
Approved on: 2021-12-13
Published on: 2022-07-11
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