The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]


Variant: NM_000527.5(LDLR):c.1920C>T (p.Asn640=)

CA037448

237869 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
UUID: 02241ae1-0fc0-41f4-ba1c-60a421eac6b6
Approved on: 2023-01-27
Published on: 2023-04-01

HGVS expressions

NM_000527.5:c.1920C>T
NM_000527.5(LDLR):c.1920C>T (p.Asn640=)
NC_000019.10:g.11120166C>T
CM000681.2:g.11120166C>T
NC_000019.9:g.11230842C>T
CM000681.1:g.11230842C>T
NC_000019.8:g.11091842C>T
NG_009060.1:g.35786C>T
ENST00000558518.6:c.1920C>T
ENST00000252444.9:n.2174C>T
ENST00000455727.6:c.1416C>T
ENST00000535915.5:c.1797C>T
ENST00000545707.5:c.1539C>T
ENST00000557933.5:c.1920C>T
ENST00000558013.5:c.1920C>T
ENST00000558518.5:c.1920C>T
ENST00000559340.1:n.501C>T
NM_000527.4:c.1920C>T
NM_001195798.1:c.1920C>T
NM_001195799.1:c.1797C>T
NM_001195800.1:c.1416C>T
NM_001195803.1:c.1539C>T
NM_001195798.2:c.1920C>T
NM_001195799.2:c.1797C>T
NM_001195800.2:c.1416C>T
NM_001195803.2:c.1539C>T
More

Benign

Met criteria codes 4
BP4 BP7 BS3_Supporting BA1
Not Met criteria codes 5
BP2 PS4 PP1 PP4 BS4

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5 (LDLR):c.1920C>T (p.Asn640=) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1, BP4, BP7, BS3_Supporting) 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: BA1: FAF=0.03838 in Ashkenazi Jewish population in gnomAD (gnomAD 2.1.1). BP4: No REVEL, splicing evaluation required. A) not in limit. B) does not create AG or GT. C) there is a GT nearby. Var cryptic score/Wt cryptic score=0.69, it is not above 1.1, and Var cryptic score/Wt score= -0.80, it is not above 0.9. Variant is not predicted to alter splicing. BP7: Variant is synonymous and meets BP4. BS3_Supporting: Level 3 assay with heterozygous patients’ lymphocytes, RNA assays shown normal LDLR transcripts, reported by Medeiros et al, 2016, from Instituto Nacional de Saude Doutor Ricardo Jorge, Lisbon, Portugal, PMID 26020417. Functional data is consistent with no damaging effect. PP4, PS4 not met: Variant did not meet PM2. PP1 not met: There are 2 relatives without the variant had LDL-C <50th percentile in 1 family, however the index case did not meet Simon Broome criteria for FH diagnosis, reported in VCI from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. BS4 not met: There are 2 relatives without the variant had LDL-C >75th percentile in 1 family, however the index case did not meet Simon Broome criteria for FH diagnosis, and there is no instance where an unaffected family member carries the variant, reported in VCI from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. BP2 not met: Variant identified in an index case with heterozygous FH phenotype and an unspecified LDLR variant with unknown pathogenicity and phase, reported in VCI from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France.
Met criteria codes
BP4
No REVEL, splicing evaluation required. A) not in limit. B) does not create AG or GT. C) there is a GT nearby. Var cryptic score/Wt cryptic score=0.69, it is not above 1.1, and Var cryptic score/Wt score= -0.80, it is not above 0.9. Variant is not predicted to alter splicing.
BP7
Variant is synonymous and meets BP4.
BS3_Supporting
Level 3 assay with heterozygous patients’ lymphocytes, RNA assays shown normal LDLR transcripts, reported by Medeiros et al, 2016, from Instituto Nacional de Saude Doutor Ricardo Jorge, Lisbon, Portugal, PMID 26020417. Functional data is consistent with no damaging effect.
BA1
FAF=0.03838 in Ashkenazi Jewish population in gnomAD (gnomAD 2.1.1).
Not Met criteria codes
BP2
Variant identified in an index case with heterozygous FH phenotype and an unspecified LDLR variant with unknown pathogenicity and phase, reported in VCI from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France.
PS4
Variant did not meet PM2.
PP1
There are 2 relatives without the variant had LDL-C <50th percentile in 1 family, however the index case did not meet Simon Broome criteria for FH diagnosis, reported in VCI from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.
PP4
Variant did not meet PM2.
BS4
There are 2 relatives without the variant had LDL-C >75th percentile in 1 family, however the index case did not meet Simon Broome criteria for FH diagnosis, and there is no instance where an unaffected family member carries the variant, reported in VCI from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.
Curation History
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