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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Variant: NM_000527.5(LDLR):c.269A>C (p.Asp90Ala)

CA404075695

440555 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 484e1059-d6ac-4816-9757-dbdb0ed3bed2

HGVS expressions

NM_000527.5:c.269A>C
NM_000527.5(LDLR):c.269A>C (p.Asp90Ala)
NC_000019.10:g.11102742A>C
CM000681.2:g.11102742A>C
NC_000019.9:g.11213418A>C
CM000681.1:g.11213418A>C
NC_000019.8:g.11074418A>C
NG_009060.1:g.18362A>C
ENST00000558518.6:c.269A>C
ENST00000252444.9:n.523A>C
ENST00000455727.6:c.269A>C
ENST00000535915.5:c.190+2397A>C
ENST00000545707.5:c.269A>C
ENST00000557933.5:c.269A>C
ENST00000557958.1:n.355A>C
ENST00000558013.5:c.269A>C
ENST00000558518.5:c.269A>C
NM_000527.4:c.269A>C
NM_001195798.1:c.269A>C
NM_001195799.1:c.190+2397A>C
NM_001195800.1:c.269A>C
NM_001195803.1:c.269A>C
NM_001195798.2:c.269A>C
NM_001195799.2:c.190+2397A>C
NM_001195800.2:c.269A>C
NM_001195803.2:c.269A>C

Likely Pathogenic

Met criteria codes 4
PM5_Strong PP4 PP3 PM2
Not Met criteria codes 22
PS2 PS4 PS3 PS1 PVS1 PP1 PP2 BA1 PM6 BS4 BS3 BS1 PM3 PM1 PM4 BS2 BP5 BP7 BP2 BP3 BP4 BP1

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.269A>C (p.Asp90Ala) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM5_Strong, PM2, PP3 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: PM5_Strong - 4 other missense variants is the same codon: - NM_000527.5(LDLR):c.268G>A (p.Asp90Asn) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.268G>T (p.Asp90Tyr) - classified as Likely pathogenic​ by the FH VCEP, with these guidelines - NM_000527.5(LDLR):c.269A>G (p.Asp90Gly) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.270T>A (p.Asp90Glu) - Pathogenic by these guidelines There are 3 variants classified as Pathogenic by these guidelines, so PM5_Strong is met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PP3 - REVEL = 0.964. It is above 0.75, so PP3 is met PP4 - Variant meets PM2, and was identified in 1 index case with SB criteria for FH (The clinical diagnosis of hoFH was confirmed on the basis of total cholesterol >500 mg/dl at the time of diagnosis, the presence of xanthomas at an early age, and the presence of primary hypercholesterolemia in the probands’ parents or other first degree relatives. This case had total cholesterol 840mg/dl at 3 years of age) from PMID 19026292 (Kolansky et al., 2008), USA so PP4 is met
Met criteria codes
PM5_Strong
4 other missense variants is the same codon: - NM_000527.5(LDLR):c.268G>A (p.Asp90Asn) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.268G>T (p.Asp90Tyr) - classified as Likely pathogenic​ by the FH VCEP, with these guidelines - NM_000527.5(LDLR):c.269A>G (p.Asp90Gly) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.270T>A (p.Asp90Glu) - Pathogenic by these guidelines There are 3 variants classified as Pathogenic by these guidelines, so PM5_Strong is met.
PP4
Variant meets PM2, and was identified in: - 1 index case with SB criteria for FH (The clinical diagnosis of hoFH was confirmed on the basis of total cholesterol >500 mg/dl at the time of diagnosis, the presence of xanthomas at an early age, and the presence of primary hypercholesterolemia in the probands’ parents or other firstdegree relatives. This case had total cholesterol 840mg/dl at 3 years of age) from PMID 19026292 (Kolansky et al., 2008), USA so PP4 is met
PP3
REVEL = 0.964. It is above 0.75, so PP3 is met
PM2
This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met
Not Met criteria codes
PS2
no case data
PS4
Variant meets PM2, and was identified in: - 1 index case with SB criteria for FH (The clinical diagnosis of hoFH was confirmed on the basis of total cholesterol >500 mg/dl at the time of diagnosis, the presence of xanthomas at an early age, and the presence of primary hypercholesterolemia in the probands’ parents or other firstdegree relatives. This case had total cholesterol 840mg/dl at 3 years of age) from PMID 19026292 (Kolansky et al., 2008), USA not enough, so not met
PS3
no functional study performed
PS1
no other variant leads to the same amino acid change in the same codon, so not met
PVS1
variant is missense and not in initiation codon, so not met
PP1
no case data
PP2
not applicable
BA1
This variant is absent from gnomAD (gnomAD v2.1.1), so not met
PM6
no case data
BS4
no case data
BS3
no functional study performed
BS1
This variant is absent from gnomAD (gnomAD v2.1.1), so not met
PM3
Variant meets PM2, but there are no case data
PM1
Variant is not in exon 4 and does not alter Cys, so not met
PM4
variant is missense, so not met
BS2
no case data
BP5
not applicable
BP7
variant is missense, so not met
BP2
no case data
BP3
not applicable
BP4
REVEL = 0.964. It is not below 0.50, so not met
BP1
not applicable
Approved on: 2022-08-28
Published on: 2022-08-28
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