Evidence Repository - Clinical Genome Resources

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.970G>A (p.Gly324Ser)

CA023801

161263 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: ffcac230-1fce-4800-8865-926e499ad6fc

Approved on: 2021-06-23

Published on: 2021-06-24

HGVS expressions

NM_000527.5:c.970G>A

NM_000527.5(LDLR):c.970G>A (p.Gly324Ser)

NC_000019.10:g.11110681G>A

CM000681.2:g.11110681G>A

NC_000019.9:g.11221357G>A

CM000681.1:g.11221357G>A

NC_000019.8:g.11082357G>A

NG_009060.1:g.26301G>A

ENST00000558518.6:c.970G>A

ENST00000252444.9:n.1224G>A

ENST00000455727.6:c.466G>A

ENST00000535915.5:c.847G>A

ENST00000545707.5:c.589G>A

ENST00000557933.5:c.970G>A

ENST00000558013.5:c.970G>A

ENST00000558518.5:c.970G>A

ENST00000560467.1:n.541-833G>A

NM_000527.4:c.970G>A

NM_001195798.1:c.970G>A

NM_001195799.1:c.847G>A

NM_001195800.1:c.466G>A

NM_001195803.1:c.589G>A

NM_001195798.2:c.970G>A

NM_001195799.2:c.847G>A

NM_001195800.2:c.466G>A

NM_001195803.2:c.589G>A

Benign

BS2 BP2 BA1 PP1 PP3

BS3 BS4 BS1 BP5 BP7 BP3 BP4 BP1 PVS1 PS2 PS4 PS1 PS3 PP4 PP2 PM3 PM4 PM1 PM5 PM6 PM2

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.970G>A (p.Gly324Ser) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1, BS2, BP2, PP1 and PP3) 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: BA1 - FAF = 0.01153 (1.153%) in African/African American exomes (gnomAD v2.1.1). BS2 - Identified in 4 heterozygous non-affected family members from different labs. BP2 - variant identified 1 index case with heterozygous FH phenotype who is double heterozygous with NM_000384.3(APOB):c.10580G>A p.Arg3527Gln (ClinVar ID 17890) - classified as Pathogenic by the general ACMG guidelines (Chora et al., 2018). PP1 - variant segregates with phenotype in 2 informative meiosis in 1 family from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. PP3 - REVEL = 0.815. Variant has 1 stand alone, 1 Strong and 1 Supporting evidence codes towards Benign, enough to classify as Benign, and only 2 Supporting codes towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Benign.

BS2

identified in 4 heterozygous non-affected family members from different labs (Robarts Research Institute and Laboratory of Genetics and Molecular Cardiology). --- BS2 is Met

BP2

variant identified in - 1 index case with heterozygous FH phenotype from GeneDx Inc. (#)2 with another LDLR variant 'LDLR PATH HET (phase unknown)'. --- 2nd variant is not specified, so BP2 is Not Met - 2 index cases from Laboratory of Genetics and Molecular Cardiology with other variants, but in cis, so BP2 is Not Met - 1 index case with phenotype of Heterozygous FH from University of British Columbia with also the NM_000527.5(LDLR):c.301G>A p.Glu101Lys variant (ClinVar ID 161266) -- classified as Likely pathogenic by these guidelines, so BP2 is not met - 1 index case with heterozygous FH phenotype from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge is double heterozygous with NM_000384.3(APOB):c.10580G>A p.Arg3527Gln (ClinVar ID 17890) - classified as Pathogenic by the general ACMG guidelines (Chora et al., 2018) --- BP2 is Met

BA1

FAF = 0.01153 (1.153%) in African/African American exomes (gnomAD v2.1.1). FAF is above 0.5%, so BA1 is Met.

PP1

variant segregates with phenotype in 2 informative meiosis in 1 family from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge: 2 affected family members have the variant. --- PP1 is Met

PP3

REVEL = 0.815. It is above 0.75, so PP3 is Met

BS3

no functional assays performed, not applicable

BS4

no non-segregations were identified, so BS4 is Not Met

BS1

FAF = 0.01153 (1.153%) in African/African American exomes (gnomAD v2.1.1). FAF is above 0.2%, but BA1 is Met, so BS1 is Not Met

BP5

Not applicable

BP7

Missense variant, so BP7 is not applicable

BP3

Not applicable

BP4

REVEL = 0.815. It is not below 0.15 and PP3 is Met, so BP4 is Not Met

BP1

Not applicable

PVS1

Missense variant, PVS1 Not Met

PS2

no de novo cases were identified, so PS2 is Not Met

PS4

variant does not meet PM2, so PS4 is Not Met

PS1

No more reported missense variants in same codon, PS1 is Not Met

PS3

no functional assays performed, not applicable

PP4

Variant does not meet PM2, so PP4 is Not Met

PP2

Not applicable

PM3

not identified in individuals with other variants and phenotype of Homozygous FH ---- PM3 is Not Met

PM4

Missense variant, not applicable

PM1

Missense at codon 324. PM2 is Not Met, it is not exon 4 or any of the 60 Cys residues listed, so PM1 is Not Met

PM5

One more missense variant in the same codon: (1)NM_000527.5(LDLR):c.970G>T (p.Gly324Cys) (ClinVar ID 920048) - classified as VUS by these guidelines so PM5 is not met

PM6

no de novo cases were identified, so PM6 is Not Met

PM2

PopMax MAF = 0.01357 (1.36%) in African/African American exomes (gnomAD v2.1.1). MAF is not under 0.02%, so PM2 is Not Met

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