Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000237296 | SCV004022391 | uncertain significance | Hypercholesterolemia, familial, 1 | 2023-03-20 | reviewed by expert panel | curation | The NM_000527.4(LDLR):c.-156C>T variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PS3_supporting, PS4_supporting, PP4) 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 - This variant is absent from gnomAD (gnomAD v2.1.1). PS3_supporting - Level 3 assay: PMID 31395865: Heterologous cells, luciferase assays - result - luciferase activity 15-17% of wild-type (repressing variant). ---- functional study is consistent with damaging effect. PS4_supporting - Variant meets PM2 and is identified in 2 index cases with definite FH: 1 index case with CT=439, LDL=377, severe CAD and Achilles tendon xanthomata from Germany (PMID: 14974088), and 1 index case with LDL >13 mmol/L, pCHD and tendon xanthomas from Italy (PMID: 31947532). PP4 - Variant meets PM2 and is identified in 2 index cases with definite FH (see PS4 for details), after alternative causes for high cholesterol were excluded. |
LDLR- |
RCV000237296 | SCV000294377 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Invitae | RCV000813804 | SCV000954180 | uncertain significance | Familial hypercholesterolemia | 2022-03-21 | criteria provided, single submitter | clinical testing | This variant occurs in a non-coding region of the LDLR gene. It does not change the encoded amino acid sequence of the LDLR protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hypercholesterolemia (PMID: 14974088, 21382890, 28104544, 32977124, 33740630). ClinVar contains an entry for this variant (Variation ID: 250942). Studies have shown that this variant alters LDLR gene expression (PMID: 31395865). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
Ambry Genetics | RCV002401928 | SCV002708449 | likely pathogenic | Cardiovascular phenotype | 2019-01-14 | criteria provided, single submitter | clinical testing | The c.-156C>T variant is located in the 5' untranslated region (5’ UTR) of the LDLR gene. This variant results from a C to T substitution 156 nucleotides upstream from the first translated codon, and is located in the sterol regulatory element (SRE-1). This variant was reported to occur in the homozygous state in a 44 year-old individual with severe coronary artery disease, LDL-C of 377mg/dL, Achilles tendon xanthoma, periorbital xanthelasma, and sudden death who also had a family history of heart attack, sudden death, and hypercholesterolemia. A reportedly less severely affected sibling was heterozygous for the variant (Dedoussis GV et al. Hum. Mutat., 2004 Mar;23:285-6). In another study, this variant was detected in an individual from a familial hypercholesterolemia cohort, with LDL-C of 6.72mmol/L (Durst R et al. Atherosclerosis, 2017 02;257:55-63). Another alteration at this nucleotide position (c.156C>A) has been shown to impact transcriptional regulation of LDLR expression (Smith JR et al. J. Biol. Chem. 1990;265(4):2306-10; Wang X et al. J. Biol. Chem. 1993;268(19):14497-504). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
Ce |
RCV003417847 | SCV004137803 | uncertain significance | not provided | 2022-12-01 | criteria provided, single submitter | clinical testing | LDLR: PM1, PM2 |