Submissions for variant NM_000527.5(LDLR):c.367T>C (p.Ser123Pro)

dbSNP: rs879254495

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV001042933	SCV000294662	uncertain significance	Familial hypercholesterolemia	2024-02-19	criteria provided, single submitter	literature only	Reevaluation of the ACMG criteria for this entry, only PM2 can be scored. Therefore, the classification is for Uncertain significance.
Invitae	RCV001042933	SCV001206642	uncertain significance	Familial hypercholesterolemia	2023-11-02	criteria provided, single submitter	clinical testing	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; Invitae). ClinVar contains an entry for this variant (Variation ID: 251181). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV001042933	SCV001353457	uncertain significance	Familial hypercholesterolemia	2019-12-01	criteria provided, single submitter	clinical testing	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.
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000237827	SCV001653589	likely pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing	Reduced activity, in stimulated T- and EBV-transformed B-lymphocytes (with c.1478_1479delCT).
Ambry Genetics	RCV003165664	SCV003912560	uncertain significance	Cardiovascular phenotype	2022-12-06	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV003313061	SCV004012428	uncertain significance	not provided	2023-06-21	criteria provided, single submitter	clinical testing	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)