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]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000527.5(LDLR):c.1868T>C (p.Ile623Thr)

CA037264

369855 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 0cf2579d-f345-4bf4-b577-f2f424de39fc
Approved on: 2023-04-28
Published on: 2023-04-30

HGVS expressions

NM_000527.5:c.1868T>C
NM_000527.5(LDLR):c.1868T>C (p.Ile623Thr)
NC_000019.10:g.11120114T>C
CM000681.2:g.11120114T>C
NC_000019.9:g.11230790T>C
CM000681.1:g.11230790T>C
NC_000019.8:g.11091790T>C
NG_009060.1:g.35734T>C
ENST00000252444.10:c.2126T>C
ENST00000559340.2:c.1728T>C
ENST00000560467.2:c.1748T>C
ENST00000558518.6:c.1868T>C
ENST00000252444.9:c.2122T>C
ENST00000455727.6:c.1364T>C
ENST00000535915.5:c.1745T>C
ENST00000545707.5:c.1487T>C
ENST00000557933.5:c.1868T>C
ENST00000558013.5:c.1868T>C
ENST00000558518.5:c.1868T>C
ENST00000559340.1:c.449T>C
NM_000527.4:c.1868T>C
NM_001195798.1:c.1868T>C
NM_001195799.1:c.1745T>C
NM_001195800.1:c.1364T>C
NM_001195803.1:c.1487T>C
NM_001195798.2:c.1868T>C
NM_001195799.2:c.1745T>C
NM_001195800.2:c.1364T>C
NM_001195803.2:c.1487T>C
More

Uncertain Significance

Met criteria codes 3
BP2 PP4 PM2
Not Met criteria codes 18
BP4 BP3 PS1 PS2 PS3 PS4 PVS1 PP1 PP3 PM1 PM3 PM4 PM6 BA1 BS2 BS1 BS4 BS3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.1868T>C (p.Ile623Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP4, and BP2 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: PopMax MAF = 0.00005 (0.005%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). So, PM2 is met. PP4: Variant meets PM2 and is identified in 1 case with Simon-Broome criteria of possible FH from Robarts Research Institute. So, PP4 is met. BP2: 1 individual from Robarts Research Institute with APOB c.10580G>A variant. Phenotype LDL 5.82 mmol/L - Heterozygous phenotype, c.10580G>A - Pathogenic using the general ACMG guidelines. So BP2 is met.
Met criteria codes
BP2
1 individual from Robarts Research Institute with APOB c.10580G>A variant. Phenotype LDL 5.82 mmol/L - Heterozygous phenotype, c.10580G>A - Pathogenic using the general ACMG guidelines. So BP2 is met.
PP4
Variant meets PM2 and is identified in 1 case with Simon-Broome criteria of possible FH from Robarts Research Institute. So, PP4 is met.
PM2
PopMax MAF = 0.00005 (0.005%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). So, PM2 is met.
Not Met criteria codes
BP4
REVEL=0.585. It is above 0.5.
BP3
no in-frame deletions/insertions
PS1
No other missense variant with the same amino acid change.
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No data available.
PS4
Variant meets PM2 and is identified in 1 case with Simon-Broome criteria of possible FH from Robarts Research Institute
PVS1
Not a null variant
PP1
No data available
PP3
REVEL=0.585. It is not above 0.75, so splicing evaluation needed. Functional data on splicing not available. A) variant not on limits. B) variant is exonic and at least 50bp upstream from the canonical donor site, but it does not create AG. C) There is an AG nearby. MES scores: variant cryptic = -3.31, wt cryptic = -2.30, canonical acceptor = 9.58. Ratio variant cryptic/wt cryptic: -3.31/-2.30 = 1.44 --- it is above 1.1 Ratio variant cryptic/canonical acceptor: -3.31/9.58 = -0.34--- it is below 0.9 Variant is not predicted to alter splicing.
PM1
Not in exon 4. Not a cysteine residue.
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
no in-frame deletions/insertions
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
PopMax FAF= 0.00001121.
BS2
No data available.
BS1
PopMax FAF= 0.00001121.
BS4
No data available
BS3
No data available.
Curation History
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