NM_000527.5(LDLR):c.1085A>C (p.Asp362Ala) AND Hypercholesterolemia, familial, 1 - ClinVar (2024)

Somatic classification
of clinical impact:

None

Review status:

(0/4)

no assertion criteria provided

Somatic classification
of oncogenicity:

None

Review status:

(0/4)

no assertion criteria provided

NM_000527.5(LDLR):c.1085A>C (p.Asp362Ala)

Gene:

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

• Chr19: 11111538 (on Assembly GRCh38)
• Chr19: 11222214 (on Assembly GRCh37)

Preferred name:

NM_000527.5(LDLR):c.1085A>C (p.Asp362Ala)

Other names:

NP_000518.1:p.D362A; NM_000527.5(LDLR):c.1085A>C

HGVS:

• NC_000019.10:g.11111538A>C
• NG_009060.1:g.27158A>C
• NM_000527.5:c.1085A>CMANE SELECT
• NM_001195798.2:c.1085A>C
• NM_001195799.2:c.962A>C
• NM_001195800.2:c.581A>C
• NM_001195803.2:c.704A>C
• NP_000518.1:p.Asp362Ala
• NP_000518.1:p.Asp362Ala
• NP_001182727.1:p.Asp362Ala
• NP_001182728.1:p.Asp321Ala
• NP_001182729.1:p.Asp194Ala
• NP_001182732.1:p.Asp235Ala
• LRG_274t1:c.1085A>C
• LRG_274:g.27158A>C
• LRG_274p1:p.Asp362Ala
• NC_000019.9:g.11222214A>C
• NM_000527.4(LDLR):c.1085A>C
• NM_000527.4:c.1085A>C
• c.1085A>C

Protein change:

D194A

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000792; dbSNP: rs138315511

NCBI 1000 Genomes Browser:

rs138315511

Molecular consequence:

• NM_000527.5:c.1085A>C - missense variant - [Sequence Ontology: SO:0001583]
• NM_001195798.2:c.1085A>C - missense variant - [Sequence Ontology: SO:0001583]
• NM_001195799.2:c.962A>C - missense variant - [Sequence Ontology: SO:0001583]
• NM_001195800.2:c.581A>C - missense variant - [Sequence Ontology: SO:0001583]
• NM_001195803.2:c.704A>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

47

"The variant was detected in a patient diagnosed with FH; controls not tested."

PubMed [ID: 16250003]

"The variant was detected in two patients diagnosed with FH; controls not tested."

PubMed [ID: 15823288]

"The variant was detected in 5 patients diagnosed with FH; One Pt is compound heterozygous for the variant and c.21405G>A (VUS); unknown if detected in controls."

PubMed [ID: 16542394]

Description

Converted during submission to Likely pathogenic.

Description

MAF =<0.3%, likely pathogenic based on the integrative in-silico score, previously reported as P/LP in the literature

Description

The p.Asp362Ala variant in LDLR has been reported in 8 individuals (including 5 Danish and 1 Dutch individuals) with Familial Hypercholesterolemia (PMID: 27765764, 11810272, 16542394, 28145427), and has been identified in 0.01782% (23/129086) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs138315511). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as a benign variant, likely benign variant, VUS, and likely pathogenic variant (Variation ID: 36452). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Moderate, PP3 (Richards 2015).

Description

The NM_000527.5(LDLR):c.1085A>C (p.Asp362Ala) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4 and PS4_Moderate) 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 = 0.0001782 (0.01782%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1). PS4_Moderate - Variant meets PM2 and is identified in 8 unrelated index cases (5 cases with Simon-Broome criteria of definite/possible FH published in PMID: 16542394, Denmark; at least 1 case with DLCN>=6 published in PMID: 11810272, Netherlands; 1 case with DLCN criteria >=6 from Robarts Research Institute, Canada; 1 case with Simon-Broome criteria of possible FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czechia. PP4 - Variant meets PM2 and is identified in at least one case who fufills clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded.

Description

This missense variant replaces aspartic acid with alanine at codon 362 of the LDLR protein. This variant is also known as p.Asp341Ala in the mature protein. This variant alters a conserved aspartic acid residue in the EGF-like repeat B of the LDLR protein (a.a. 355-393), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in six individuals affected with familial hypercholesterolemia (PMID: 11810272, 15823288, 27765764, 33740630; Color internal data) and in one individual affected with isolated hypercholesterolemia (PMID: 33303402). This variant has been identified in 23/282712 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.