Submissions for variant NM_000057.4(BLM):c.1927C>T (p.Arg643Cys)

gnomAD frequency: 0.00018  dbSNP: rs373090621

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000459068	SCV000543390	uncertain significance	Bloom syndrome	2022-10-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 643 of the BLM protein (p.Arg643Cys). This variant is present in population databases (rs373090621, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with BLM-related conditions. ClinVar contains an entry for this variant (Variation ID: 405323). 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 BLM protein function. 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	RCV001013735	SCV001174358	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-09	criteria provided, single submitter	clinical testing	The p.R643C variant (also known as c.1927C>T), located in coding exon 7 of the BLM gene, results from a C to T substitution at nucleotide position 1927. The arginine at codon 643 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV002508213	SCV002817798	uncertain significance	not provided	2022-06-30	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
PreventionGenetics, part of Exact Sciences	RCV003418157	SCV004116373	uncertain significance	BLM-related condition	2023-02-21	criteria provided, single submitter	clinical testing	The BLM c.1927C>T variant is predicted to result in the amino acid substitution p.Arg643Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.035% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-91306240-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002508213	SCV004222439	uncertain significance	not provided	2023-09-18	criteria provided, single submitter	clinical testing	This variant has not been reported in individuals with BLM-related conditions in the published literature. The frequency of this variant in the general population, 0.00035 (7/19916 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Natera, Inc.	RCV000459068	SCV001461830	uncertain significance	Bloom syndrome	2020-09-16	no assertion criteria provided	clinical testing