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.760C>T (p.Gln254Ter)

CA10585116

251436 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
UUID: c8ddc916-8f19-4334-ad28-b49e531f6f19
Approved on: 2022-08-28
Published on: 2022-08-28

HGVS expressions

NM_000527.5:c.760C>T
NM_000527.5(LDLR):c.760C>T (p.Gln254Ter)
NC_000019.10:g.11106630C>T
CM000681.2:g.11106630C>T
NC_000019.9:g.11217306C>T
CM000681.1:g.11217306C>T
NC_000019.8:g.11078306C>T
NG_009060.1:g.22250C>T
ENST00000558518.6:c.760C>T
ENST00000252444.9:n.1014C>T
ENST00000455727.6:c.314-762C>T
ENST00000535915.5:c.637C>T
ENST00000545707.5:c.379C>T
ENST00000557933.5:c.760C>T
ENST00000558013.5:c.760C>T
ENST00000558518.5:c.760C>T
ENST00000558528.1:n.275C>T
ENST00000560467.1:n.360C>T
NM_000527.4:c.760C>T
NM_001195798.1:c.760C>T
NM_001195799.1:c.637C>T
NM_001195800.1:c.314-762C>T
NM_001195803.1:c.379C>T
NM_001195798.2:c.760C>T
NM_001195799.2:c.637C>T
NM_001195800.2:c.314-762C>T
NM_001195803.2:c.379C>T

Pathogenic

Met criteria codes 4
PM2 PM3 PVS1 PP4
Not Met criteria codes 22
PM6 PM1 PM4 PM5 BS2 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS4 PS3 PS1 PP1 PP3 PP2 BA1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.760C>T (p.Gln254Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1, PM2, PM3 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 leads to stop at codon 254. It is 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. PM3 - variant meets PM2 and was identified in 1 index case (Patient F3) with LDLc 18.21 mmol/l and compound heterozygote with NM_000527.5(LDLR):c.1216C>A (p.Arg406=) from Du et al. 2016 (PMID: 28028493). -- 2nd variant is classified as Likely Pathogenic by these guidelines and patient has phenotype of homozygous FH, so PM3 is met. PP4 - variant meets PM2 and was identified in 1 index case with DLCN at least 14 (LDL of 18.21mmol/L and xanthomas), from Du et al. 2016 (PMID: 28028493), China, so PP4 is met.
Met criteria codes
PM2
This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met
PM3
variant meets PM2 and was identified in 1 index case (Patient F3) with LDLc 18.21 mmol/l and compound heterozygote with NM_000527.5(LDLR):c.1216C>A (p.Arg406=) from Du et al. 2016 (PMID: 28028493). -- 2nd variant is classified as Likely Pathogenic by these guidelines and patient has phenotype of homozygous FH, so PM3 is met
PVS1
Variant leads to stop at codon 254. It is amino-terminal of amino acid 830, so PVS1 is met
PP4
variant meets PM2 and was identified in - 1 index case with DLCN at least 14 (LDL of 18.21mmol/L and xanthomas), from Du et al. 2016 (PMID: 28028493), China. so PP4 is met
Not Met criteria codes
PM6
no de novo occurrence
PM1
variant is nonsense, so not applicable
PM4
variant is nonsense, so not applicable
PM5
variant is nonsense, so not applicable
BS2
variant was not identified in normolipidemic individuals, so not met
BS4
no segregation data
BS3
this variant was not studied in functional studies
BS1
This variant is absent from gnomAD (gnomAD v2.1.1).
BP5
not applicable
BP7
variant is nonsense, so not applicable
BP2
not identified in index cases with other variants and phenotype of heterozygous FH, so not met
BP3
not applicable
BP4
variant meets PVS1, so not applicable
BP1
not applicable
PS2
no de novo occurrence
PS4
variant meets PM2 and was identified in - 1 index case with DLCN at least 14 (LDL of 18.21mmol/L and xanthomas), from Du et al. 2016 (PMID: 28028493), China. not enough, so not met
PS3
this variant was not studied in functional studies
PS1
variant is nonsense, so not applicable
PP1
no segregation data
PP3
variant meets PVS1, so not applicable
PP2
not applicable
BA1
This variant is absent from gnomAD (gnomAD v2.1.1).
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