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]
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Variant: NM_000527.5(LDLR):c.1618G>T (p.Ala540Ser)

CA10585529

251938 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 6f238252-988b-448e-966f-3865fda9608c
Approved on: 2022-08-28
Published on: 2022-08-28

HGVS expressions

NM_000527.5:c.1618G>T
NM_000527.5(LDLR):c.1618G>T (p.Ala540Ser)
NC_000019.10:g.11116125G>T
CM000681.2:g.11116125G>T
NC_000019.9:g.11226801G>T
CM000681.1:g.11226801G>T
NC_000019.8:g.11087801G>T
NG_009060.1:g.31745G>T
ENST00000558518.6:c.1618G>T
ENST00000252444.9:n.1872G>T
ENST00000455727.6:c.1114G>T
ENST00000535915.5:c.1495G>T
ENST00000545707.5:c.1237G>T
ENST00000557933.5:c.1618G>T
ENST00000558013.5:c.1618G>T
ENST00000558518.5:c.1618G>T
ENST00000559340.1:n.339G>T
NM_000527.4:c.1618G>T
NM_001195798.1:c.1618G>T
NM_001195799.1:c.1495G>T
NM_001195800.1:c.1114G>T
NM_001195803.1:c.1237G>T
NM_001195798.2:c.1618G>T
NM_001195799.2:c.1495G>T
NM_001195800.2:c.1114G>T
NM_001195803.2:c.1237G>T
More

Likely Pathogenic

Met criteria codes 4
PP4 PP3 PM5 PM2
Not Met criteria codes 22
BS4 BS3 BS1 BS2 BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS4 PS3 PS1 PP1 PP2 PVS1 PM3 PM1 PM4 PM6 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.1618G>T (p.Ala540Ser) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, 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 - variant was not identified in gnomAD (gnomAD v2.1.1), so met. PM5 - 1 other missense variant in the same codon: - NM_000527.5(LDLR):c.1618G>A (p.Ala540Thr) - 2 stars, Pathogenic/Likely pathogenic - Pathogenic by these guidelines so PM5 is met. PP3 - REVEL = 0.821. It is above 0.75, so PP3 is met. PP4 - variant meets PM2 and was identified in: - at least 1 index case with definite FH ((in the paper: "All patients were clinically diagnosed with definite heterozygous hypercholesterolemia by cardiologists and internists using a uniform protocol and internationally accepted criteria [Defesche, 2000].") from PMID 16250003 (Fouchier et al., 2005), The Netherlands. so PP4 is met.
Met criteria codes
PP4
variant meets PM2 and was identified in: - at least 1 index case with definite FH ((in the paper: "All patients were clinically diagnosed with definite heterozygous hypercholesterolemia by cardiologists and internists using a uniform protocol and internationally accepted criteria [Defesche, 2000].") from PMID 16250003 (Fouchier et al., 2005), The Netherlands. so PP4 is met
PP3
REVEL = 0.821. It is above 0.75, so PP3 is met
PM5
1 other missense variant in the same codon: - NM_000527.5(LDLR):c.1618G>A (p.Ala540Thr) - 2 stars, Pathogenic/Likely pathogenic - Pathogenic by these guidelines so PM5 is met
PM2
This variant was not identified in gnomAD (gnomAD v2.1.1), so met
Not Met criteria codes
BS4
no segregation data
BS3
there is no functional study on this variant
BS1
This variant was not identified in gnomAD (gnomAD v2.1.1), so not met
BS2
there is no data on normolipidemic individuals
BP5
not applicable
BP7
variant is missense, so not applicable
BP2
not identified in index cases with other variants
BP3
not applicable
BP4
REVEL = 0.821. It is not below 0.50, so BP4 is not met
BP1
not applicable
PS2
no de novo occurrence
PS4
variant meets PM2 and was identified in: - at least 1 index case with definite FH ((in the paper: "All patients were clinically diagnosed with definite heterozygous hypercholesterolemia by cardiologists and internists using a uniform protocol and internationally accepted criteria [Defesche, 2000].") from PMID 16250003 (Fouchier et al., 2005), The Netherlands. not enough, so PS4 is not met
PS3
there is no functional study on this variant
PS1
no other variant leads to the same amino acid change, so not met
PP1
no segregation data
PP2
not applicable
PVS1
variant is missense and not in initiation codon, not applicable
PM3
not identified in index cases with other variants
PM1
variant is missense and meets PM2, but it is not in exon 4 and does not alter Cys, so not met
PM4
variant is missense, so not applicable
PM6
no de novo occurrence
BA1
This variant was not identified in gnomAD (gnomAD v2.1.1), so not met
Curation History
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