Submissions for variant NM_000057.4(BLM):c.1064C>G (p.Pro355Arg)

dbSNP: rs1022898915

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000535187	SCV000623220	uncertain significance	Bloom syndrome	2022-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 355 of the BLM protein (p.Pro355Arg). This variant is not present in population databases (gnomAD no frequency). 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: 454061). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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	RCV001009800	SCV001169914	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-25	criteria provided, single submitter	clinical testing	The p.P355R variant (also known as c.1064C>G), located in coding exon 4 of the BLM gene, results from a C to G substitution at nucleotide position 1064. The proline at codon 355 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is poorly 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.
Genetic Services Laboratory, University of Chicago	RCV001821467	SCV002068073	uncertain significance	not specified	2020-04-16	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BLM gene demonstrated a sequence change, c.1064C>G, in exon 5 that results in an amino acid change, p.Pro355Arg. This sequence change does not appear to have been previously described in patients with BLM-related disorders and has also not been described in the population databases (ExAC and gnomAD). The p.Pro355Arg change affects a poorly conserved amino acid residue located in a domain of the BLM protein that is not known to be functional. The p.Pro355Arg substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Pro355Arg change remains unknown at this time.
Natera, Inc.	RCV000535187	SCV001466156	uncertain significance	Bloom syndrome	2020-09-04	no assertion criteria provided	clinical testing