ClinVar Genomic variation as it relates to human health

The NM_000527.5(LDLR):c.1875C>T (p.Asn625=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying evidence codes PP1, BP2, BP4, and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). Variant has 3 supporting evidence codes towards Benign, enough to classify as Likely benign, and only 1 supporting evidence codes towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Likely benign. The supporting evidence is as follows: PP1: Variant segregates with FH phenotype in 2 informative meioses in 1 families from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge. So PP1 is met. BP2: 1 individual from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge with LDLR c.1598G>A. Phenotype LDL 168mg/dl under statins - Htz phenotype, c.1598G>A - Pathogenic by these guidelines. BP4: No REVEL available, splicing evaluation needed. 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, but it does not create AG. C) there is an AG nearby. MES scores: variant cryptic = -1.41, wt cryptic = -2.30, canonical acceptor = 9.58. Ratio variant cryptic/wt cryptic: -1.41/-2.30 = 0.61 --- it is not above 1.1 Ratio variant cryptic/canonical acceptor: -1.41/9.58 = 0.15--- it is not above 0.9 Variant is not predicted to alter splicing. So BP4 is met. BP7: Variant is synonymous and meets BP4.

0/95 non-FH individuals

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

MAF =<0.3%

This variant is associated with the following publications: (PMID: 22881376, 18065781, 17347910, 25985138)

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).