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]
  • See Evidence submitted by expert panel for details.

Variant: NM_000527.5(LDLR):c.758G>A (p.Arg253Gln)

CA029258

843407 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 3960bd6f-ba20-490b-8aa9-fd6487a9bf2e
Approved on: 2022-04-22
Published on: 2022-04-22

HGVS expressions

NM_000527.5:c.758G>A
NM_000527.5(LDLR):c.758G>A (p.Arg253Gln)
NC_000019.10:g.11106628G>A
CM000681.2:g.11106628G>A
NC_000019.9:g.11217304G>A
CM000681.1:g.11217304G>A
NC_000019.8:g.11078304G>A
NG_009060.1:g.22248G>A
ENST00000558518.6:c.758G>A
ENST00000252444.9:n.1012G>A
ENST00000455727.6:c.314-764G>A
ENST00000535915.5:c.635G>A
ENST00000545707.5:c.377G>A
ENST00000557933.5:c.758G>A
ENST00000558013.5:c.758G>A
ENST00000558518.5:c.758G>A
ENST00000558528.1:n.273G>A
ENST00000560467.1:n.358G>A
NM_000527.4:c.758G>A
NM_001195798.1:c.758G>A
NM_001195799.1:c.635G>A
NM_001195800.1:c.314-764G>A
NM_001195803.1:c.377G>A
NM_001195798.2:c.758G>A
NM_001195799.2:c.635G>A
NM_001195800.2:c.314-764G>A
NM_001195803.2:c.377G>A
More

Uncertain Significance

Met criteria codes 2
BP4 PM2
Not Met criteria codes 20
BS4 BS3 BS1 BS2 BP7 BP2 PVS1 PS2 PS4 PS3 PS1 BA1 PP4 PP1 PP3 PM6 PM4 PM3 PM1 PM5

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.758G>A (p.Arg253Gln) variant is classified as Uncertain significance – insufficient evidence for Familial Hypercholesterolemia by applying evidence PM2 and BP4 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 = 0.000096 (0.0096%) in Ashkenazi Jewish exomes+genomes (gnomAD v2.1.1). BP4 - REVEL = 0.44; score is below 0.5 threshold, splicing evaluation required. Functional data on splicing not available. Category B) - variant is exonic and at least 50bp upstream from the canonical donor site, and creates an AG. MES scores: de novo variant = 0; canonical acceptor site = 10.79; ratio = 0/10.79 = 0; this is below the threshold of 0.8 and therefore this variant is predicted to not affect splicing. Note: two other missense variants at this same codon have been reported: 1) NM_000527.5(LDLR):c.757C>T (p.Arg253Trp); 2) NM_000527.5(LDLR):c.758G>C (p.Arg253Pro); however, both are VUS by these LDLR guidelines (PM5 not applicable).
Met criteria codes
BP4
REVEL = 0.44; score is below 0.5 threshold, splicing evaluation required. 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, and creates an AG. MES scores: de novo variant = 0; canonical acceptor site = 10.79. Ratio de novo variant / canonical acceptor = 0/10.79 = 0; this is below the threshold of 0.8 and therefore this variant is predicted to not affect splicing.
PM2
PopMax MAF = 0.000096 (0.0096%) in Ashkenazi Jewish exomes+genomes (gnomAD v2.1.1).
Not Met criteria codes
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
REVEL = 0.44; score 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 upstream from the canonical donor site, and creates an AG. MES scores: de novo variant = 0; canonical acceptor site = 10.79. Ratio de novo variant / canonical acceptor = 0/10.79 = 0; this is below the threshold of 0.8 and therefore this variant is predicted to not affect splicing.
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
2 other missense variants in the same codon: 1) NM_000527.5(LDLR):c.757C>T (p.Arg253Trp)- VUS by these guidelines. 2) NM_000527.5(LDLR):c.758G>C (p.Arg253Pro) – VUS by these guidelines.
Curation History
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