Submissions for variant NM_000527.5(LDLR):c.731C>G (p.Ser244Cys)

gnomAD frequency: 0.00001  dbSNP: rs1208667598

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000508755	SCV004022428	uncertain significance	Hypercholesterolemia, familial, 1	2023-04-28	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.731C>G (p.Ser244Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2 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: No exome data available for this variant in gnomAD v2.1.1. Genome and exome data were available for the neighboring variant, 19-11217264-G-A(GRCh37). The c.731C>G (p.Ser244Cys) variant was present in 1/15432 European (non-Finnish) genomes. The 19-11217264-G-A(GRCh37) variant was tested in 113760 alles from European (non-Finnish) exomes. Final adjusted allele frequency: 1/( 15432+ 113760) = 0.0007740417%.
Color Diagnostics, LLC DBA Color Health	RCV001187125	SCV001353796	uncertain significance	Familial hypercholesterolemia	2020-10-07	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Ser223Cys in the mature protein) replaces serine with cysteine at codon 244 of the LDLR protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 1/31406 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001187125	SCV001413877	uncertain significance	Familial hypercholesterolemia	2021-08-27	criteria provided, single submitter	clinical testing	This sequence change replaces serine with cysteine at codon 244 of the LDLR protein (p.Ser244Cys). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with LDLR-related conditions. ClinVar contains an entry for this variant (Variation ID: 440599). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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.
AiLife Diagnostics, AiLife Diagnostics	RCV002223219	SCV002501407	uncertain significance	not provided	2021-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002383987	SCV002674385	uncertain significance	Cardiovascular phenotype	2022-12-08	criteria provided, single submitter	clinical testing	The p.S244C variant (also known as c.731C>G), located in coding exon 5 of the LDLR gene, results from a C to G substitution at nucleotide position 731. The serine at codon 244 is replaced by cysteine, an amino acid with dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Vill&eacute;ger L. Hum Mutat. 2002;20(2):81-7). 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.
Fulgent Genetics, Fulgent Genetics	RCV000508755	SCV002789710	uncertain significance	Hypercholesterolemia, familial, 1	2021-09-13	criteria provided, single submitter	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000508755	SCV000606212	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research