Submissions for variant NM_000057.4(BLM):c.3922G>A (p.Gly1308Arg)

gnomAD frequency: 0.00003  dbSNP: rs768010078

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000628625	SCV000749529	uncertain significance	Bloom syndrome	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1308 of the BLM protein (p.Gly1308Arg). This variant is present in population databases (rs768010078, gnomAD 0.006%). 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: 524764). 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 BLM protein function with a negative predictive value of 80%. 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003237958	SCV002010750	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002358750	SCV002622069	likely benign	Hereditary cancer-predisposing syndrome	2024-06-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV003237958	SCV005690171	uncertain significance	not provided	2024-08-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Natera, Inc.	RCV000628625	SCV002090625	uncertain significance	Bloom syndrome	2020-07-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004745509	SCV005366274	uncertain significance	BLM-related disorder	2024-03-27	no assertion criteria provided	clinical testing	The BLM c.3922G>A variant is predicted to result in the amino acid substitution p.Gly1308Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD and is classified as variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/524764/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.