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.232C>T (p.Arg78Cys)

CA023658

161289 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: c0820c58-696d-4193-ae01-ff55edbec638

HGVS expressions

NM_000527.5:c.232C>T
NM_000527.5(LDLR):c.232C>T (p.Arg78Cys)
ENST00000558518.6:c.232C>T
ENST00000252444.9:n.486C>T
ENST00000455727.6:c.232C>T
ENST00000535915.5:c.190+2360C>T
ENST00000545707.5:c.232C>T
ENST00000557933.5:c.232C>T
ENST00000557958.1:n.318C>T
ENST00000558013.5:c.232C>T
ENST00000558518.5:c.232C>T
NM_000527.4:c.232C>T
NM_001195798.1:c.232C>T
NM_001195799.1:c.190+2360C>T
NM_001195800.1:c.232C>T
NM_001195803.1:c.232C>T
NM_001195798.2:c.232C>T
NM_001195799.2:c.190+2360C>T
NM_001195800.2:c.232C>T
NM_001195803.2:c.232C>T
NC_000019.10:g.11102705C>T
CM000681.2:g.11102705C>T
NC_000019.9:g.11213381C>T
CM000681.1:g.11213381C>T
NC_000019.8:g.11074381C>T
NG_009060.1:g.18325C>T

Uncertain Significance

Met criteria codes 3
PS4_Supporting PP4 PM2
Not Met criteria codes 23
PS2 PS1 PS3 PP3 PP2 PP1 PM6 PM3 PM4 PM1 PM5 PVS1 BA1 BS2 BS4 BS3 BS1 BP5 BP7 BP4 BP1 BP2 BP3

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.232C>T (p.Arg78Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4_Supporting and PP4) 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: PM2 - PopMax MAF = 0.0001002 (0.010%) in South Asian exomes (gnomAD v2.1.1). PP4 - Variant meets PM2. Identified in 2 FH cases from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with Dutch Lipid Clinic score ≥ 6. PS4_supporting - Variant meets PM2. Variant identified in at least 4 unrelated index cases with Simon-Broome criteria for FH or Dutch Lipid Clinic score equal or above 6 from different labs.
Met criteria codes
PS4_Supporting
Variant meets PM2. Variant identified in at least 4 unrelated index cases with Simon-Broome criteria for FH or Dutch Lipid Clinic score equal or above 6 from different labs (at least 1 from Color, 1 from GeneDx Inc. and 2 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA)) --- PS4_Supporting is Met
PP4
Variant meets PM2. Identified in 2 FH cases from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with Dutch Lipid Clinic score ≥ 6. ---- PP4 is Met
PM2
PopMax MAF = 0.0001002 (0.010%) in South Asian exomes (gnomAD v2.1.1).
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
no functional assays performed, not applicable
PP3
REVEL = 0.707. 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 50 bp upstream of canonical donor, but it does not create AG. C) there is no AG nearby. No splicing prediction is applicable, so PP3 is Not Met
PP2
Not applicable
PP1
no family members were tested, so PP1 is Not Met
PM6
no de novo cases were identified, so PM6 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 78. 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_000527.5(LDLR):c.233G>A (p.Arg78His) (ClinVar ID 251085) - VUS by these guidelines --- variant is classified as VUS, so PM5 is Not Met.
PVS1
Missense variant, PVS1 Not Met
BA1
FAF = 0.00001897 (0.002%) in east asian exomes (gnomAD v2.1.1). FAF is not above 0.5%, so BA1 is Not Met.
BS2
no unaffected individuals identified with the variant, so BS2 is Not Met
BS4
no family members were tested, so BS4 is Not Met
BS3
no functional assays performed, not applicable
BS1
FAF = 0.00001897 (0.002%) in east asian exomes (gnomAD v2.1.1). FAF is not above 0.2%, so BS1 is Not Met
BP5
Not applicable
BP7
Missense variant, so BP7 is not applicable
BP4
REVEL = 0.707. It is not below 0.15, so BP4 is Not Met
BP1
Not applicable
BP2
not identified in individuals with other variants, so BP2 is Not Met
BP3
Not applicable
Approved on: 2021-06-07
Published on: 2021-06-24
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