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
  • See Evidence submitted by expert panel for details.

Variant: NM_000527.5(LDLR):c.1186+5G>A

CA10585344

251706 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 10d13648-0b75-444a-93f6-f1da04980d0e

HGVS expressions

NM_000527.5:c.1186+5G>A
NM_000527.5(LDLR):c.1186+5G>A
ENST00000558518.6:c.1186+5G>A
ENST00000252444.9:n.1440+5G>A
ENST00000455727.6:c.682+5G>A
ENST00000535915.5:c.1063+5G>A
ENST00000545707.5:c.805+5G>A
ENST00000557933.5:c.1186+5G>A
ENST00000558013.5:c.1186+5G>A
ENST00000558518.5:c.1186+5G>A
ENST00000560173.1:n.185+5G>A
ENST00000560467.1:n.666+5G>A
NM_000527.4:c.1186+5G>A
NM_001195798.1:c.1186+5G>A
NM_001195799.1:c.1063+5G>A
NM_001195800.1:c.682+5G>A
NM_001195803.1:c.805+5G>A
NM_001195798.2:c.1186+5G>A
NM_001195799.2:c.1063+5G>A
NM_001195800.2:c.682+5G>A
NM_001195803.2:c.805+5G>A
NC_000019.10:g.11111644G>A
CM000681.2:g.11111644G>A
NC_000019.9:g.11222320G>A
CM000681.1:g.11222320G>A
NC_000019.8:g.11083320G>A
NG_009060.1:g.27264G>A

Likely Pathogenic

Met criteria codes 4
PP4 PM2 PS3_Moderate PS4_Moderate
Not Met criteria codes 22
PP1 PP3 PP2 PM6 PM3 PM1 PM4 PM5 PVS1 BA1 BS2 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS1

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.1186+5G>A variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PS3_Moderate, PS4_Moderate 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 - No population data was found for this variant in gnomAD (gnomAD v2.1.1). PS3_moderate - Level 2 FS: PMID:21990180 - study on htz patient's lymhocytes. FACS + CSLM + Nothern blot were used. 50% biosynthetic process; 65% binding; 60% clearance. Abnormal transcript: retention of part of intron 8 causing a frameshift and premature stop codon (LDLR:p.G396fs*26) then identified by cDNA sequencing. PS4_moderate - Variant meets PM2 and was found in 8 unrelated FH cases. PP4 - Variant meets PM2. Variant found in 8 FH cases fulfilling validated clinical criteria.
Met criteria codes
PP4
Variant meets PM2. Variant found in 8 FH cases fulfilling validated clinical criteria (1 case in PMID: 12436241; 7 cases in PMID: 21990180 (DLCN 8.1±0.4)).
PM2
No population data was found for this variant in gnomAD (gnomAD v2.1.1)
PS3_Moderate
Level 2 FS: PMID:21990180 - study on htz patient's lymhocytes. FACS + CSLM + Nothern blot were used. 50% biosynthetic process; 65% binding; 60% clearance. Abnormal transcript: retention of part of intron 8 causing a frameshift and premature stop codon (LDLR:p.G396fs*26) then identified by cDNA sequencing.
PS4_Moderate
Variant meets PM2 and was found in 8 unrelated FH cases (1 case in PMID: 12436241; 7 cases in PMID: 21990180 (DLCN 8.1±0.4).
Not Met criteria codes
PP1
No family members were tested.
PP3
Functional splicing data available. Not applicable.
PP2
Not applicable.
PM6
No de novo cases were identified.
PM3
Not identified in individuals with other variants.
PM1
Intronic variant. Not applicable.
PM4
Intronic variant. Not applicable.
PM5
Intronic variant. Not applicable.
PVS1
Intronic variant. Not applicable.
BA1
No population data was found for this variant in gnomAD (gnomAD v2.1.1)
BS2
No unaffected individuals identified with the variant.
BS4
No family members were tested.
BS3
Level 3 FS: PMID:21990180 - study on htz patient's lymhocytes. FACS + CSLM + Nothern blot were used. 50% biosynthetic process; 65% binding; 60% clearance. Abnormal transcript: retention of part of intron 8 causing a frameshift and premature stop codon (LDLR:p.G396fs*26) then identified by cDNA sequencing.
BS1
No population data was found for this variant in gnomAD (gnomAD v2.1.1)
BP5
Not applicable.
BP7
Intronic variant. Not applicable.
BP2
Not identified in individuals with other variants.
BP3
Not applicable.
BP4
Functional splicing data available. Not applicable.
BP1
Not applicable.
PS2
No de novo cases were identified.
PS1
Intronic variant. Not applicable.
Approved on: 2021-06-08
Published on: 2021-06-24
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