ClinVar Genomic variation as it relates to human health

Reduced activity, in stimulated T- and EBV-transformed B-lymphocytes (with c.1478_1479delCT).

This missense variant (also known as p.Ser102Pro in the mature protein) replaces serine with proline at codon 123 of the LDLR protein. This variant occurs at a poorly conserved position of the LDLR protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two individuals affected with familial hypercholesterolemia (PMID: 19446849, 20045108). One of these individuals carried a pathogenic truncation variant in the same gene that could explain the observed phenotype (PMID: 20045108). This variant has not been identified 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.

Reevaluation of the ACMG criteria for this entry, only PM2 can be scored. Therefore, the classification is for Uncertain significance.

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 123 of the LDLR protein (p.Ser123Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of familial cholesterolemia (PMID: 19446849, 20045108, 34297352, 36229376; internal data). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. ClinVar contains an entry for this variant (Variation ID: 251181). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt LDLR protein function with a negative predictive value of 95%. This variant disrupts the p.Ser123 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 15015036), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Cells from a patient who harbored a pathogenic variant (c.1478_1479delCT) in LDLR showed residual LDLR enzyme activity of 26.1% (Romano et al., 2011); This variant is associated with the following publications: (PMID: 20045108, 32977124, 21865347, 19446849, 22881376, 23375686, 30710474)

The p.S123P variant (also known as c.367T>C), located in coding exon 4 of the LDLR gene, results from a T to C substitution at nucleotide position 367. The serine at codon 123 is replaced by proline, an amino acid with similar properties. This alteration has been reported in familial hypercholesterolemia (FH) cohorts; however, clinical details were limited (Guardamagna O et al. J Pediatr, 2009 Aug;155:199-204.e2; Romano M et al. Atherosclerosis, 2010 Jun;210:493-6). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

The LDLR c.367T>C variant is predicted to result in the amino acid substitution p.Ser123Pro. This variant has been reported in individuals with familial hypercholesterolemia (Guardamagna et al. 2009. PubMed ID: 19446849; Table S3B, Bertolini et al. 2013. PubMed ID: 23375686; Di Taranto et al. 2021. PubMed ID: 34297352). It was reported in one individual with familial hypercholesterolemia who also carried a frameshift variant in LDLR, and cells from this individual showed residual LDLR activity of 26-32% (Romano et al. 2011. PubMed ID: 21865347). This variant has not been reported in a large population database, indicating this variant is rare. Other missense variants affecting this amino acid (p.Ser123Cys, p.Ser123Thr) have also been reported in individuals with familial hypercholesterolemia (Supplementary Table 2, Tada et al. 2022. PubMed ID: 36229376; Mihaylov et al. 2004. PubMed ID: 15015036). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.