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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  • See Evidence submitted by expert panel for details.

Variant: NM_000527.5(LDLR):c.185C>T (p.Thr62Met)

CA023598

161273 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: edbf1491-cba1-4dae-b1fd-1312c3a2fb87

HGVS expressions

NM_000527.5:c.185C>T
NM_000527.5(LDLR):c.185C>T (p.Thr62Met)
ENST00000558518.6:c.185C>T
ENST00000252444.9:n.439C>T
ENST00000455727.6:c.185C>T
ENST00000535915.5:c.185C>T
ENST00000545707.5:c.185C>T
ENST00000557933.5:c.185C>T
ENST00000557958.1:n.271C>T
ENST00000558013.5:c.185C>T
ENST00000558518.5:c.185C>T
ENST00000560502.5:n.271C>T
NM_000527.4:c.185C>T
NM_001195798.1:c.185C>T
NM_001195799.1:c.185C>T
NM_001195800.1:c.185C>T
NM_001195803.1:c.185C>T
NM_001195798.2:c.185C>T
NM_001195799.2:c.185C>T
NM_001195800.2:c.185C>T
NM_001195803.2:c.185C>T
NC_000019.10:g.11100340C>T
CM000681.2:g.11100340C>T
NC_000019.9:g.11211016C>T
CM000681.1:g.11211016C>T
NC_000019.8:g.11072016C>T
NG_009060.1:g.15960C>T

Uncertain Significance

Met criteria codes 1
PP1
Not Met criteria codes 25
PS2 PS1 PS3 PS4 PM3 PM4 PM1 PM5 PM6 PM2 BA1 PVS1 BP7 BP5 BP4 BP1 BP2 BP3 BS3 BS4 BS1 BS2 PP3 PP2 PP4

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.185C>T (p.Thr62Met) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PP1) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PP1 - variant segregates with FH phenotype in 3 informative meiosis in 2 families from different labs (Laboratory of Genetics and Molecular Cardiology and Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge).
Met criteria codes
PP1
variant segregates with FH phenotype in 3 informative meiosis in 2 families from different labs (Laboratory of Genetics and Molecular Cardiology and Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge): 3 affected family members have the variant. --- PP1 is Met
Not Met criteria codes
PS2
no de novo cases were identified, so PS2 is Not Met
PS1
No variant described that leads to the same amino acid change, so PS1 is Not Met
PS3
Level 1 assays: PMID 30413722: Heterologous cells (CHO-ldlA7), FACS and western blot assays - results - Normal (90-100%) cell surface LDLR, binding (85%) and uptake (100%) ---- whole cycle is not below 70% of wild-type activity, so PS3 is Not Met
PS4
Variant does not meet PM2. so PS4 is not met
PM3
not identified in individuals with other variants, so PM3 is Not Met
PM4
Missense variant, not applicable
PM1
Missense at codon 62. PM2 is Met, but it is not exon 4 or any of the 60 Cys residues listed, so PM1 is Not Met
PM5
One more missense variant described in same codon: (1)NM_000527.4(LDLR):c.185C>G (p.Thr62Arg) (ClinVar ID 375775) - VUS by these guidelines --- PM5 is Not Met
PM6
no de novo cases were identified, so PM6 is Not Met
PM2
PopMax MAF = 0.0002541 (0.02541%) in european non-finnish exomes (gnomAD v2.1.1).
BA1
FAF = 0.0001348 (0.013%) in latino exomes (gnomAD v2.1.1). FAF is not above 0.5%, so BA1 is Not Met.
PVS1
Missense variant, PVS1 Not Met
BP7
Missense variant, so BP7 is not applicable
BP5
Not applicable
BP4
REVEL = 0.651. It is not below 0.50, so BP4 is Not Met
BP1
Not applicable
BP2
not identified in individuals with other variants, so BP2 is Not Met
BP3
Not applicable
BS3
Level 1 assays: PMID 30413722: Heterologous cells (CHO-ldlA7), FACS and western blot assays - results - Normal (90-100%) cell surface LDLR, binding (85%) and uptake (100%) ---- whole cycle is not above 90% of wild-type activity, so BS3 is Not Met
BS4
no non-segregations were identified, so BS4 is Not Met
BS1
FAF = 0.0001348 (0.013%) in latino exomes (gnomAD v2.1.1). FAF is not above 0.2%, so BS1 is Not Met.
BS2
identified in 2 heterozygous non-affected family members from different labs (Laboratory of Genetics and Molecular Cardiology and ABraOM: Brazilian genomic variants database). not enough evidence to meet BS2 --- BS2 is Not Met
PP3
REVEL = 0.651. It is not above 0.75, splicing evaluation required. Functional data on splicing not available. A) variant not on limits. B) variant is exonic and at least 50bp downstream from canonical acceptor site, but it does not create GT. C) there is a GT nearby. MES scores: variant cryptic = -8.34, wt cryptic = -5.58, canonical donor = 7.39 scores are negative, which means they are not used, PP3 is Not Met
PP2
Not applicable
PP4
Variant does not meet PM2. so PP4 is not met
Approved on: 2021-06-23
Published on: 2021-06-24
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