Submissions for variant NM_000057.4(BLM):c.44G>A (p.Arg15His)

gnomAD frequency: 0.00001  dbSNP: rs752755503

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463869	SCV000543399	uncertain significance	Bloom syndrome	2025-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 15 of the BLM protein (p.Arg15His). This variant is present in population databases (rs752755503, gnomAD 0.009%). 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: 405329). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779839	SCV000916687	uncertain significance	not specified	2018-08-31	criteria provided, single submitter	clinical testing	Variant summary: BLM c.44G>A (p.Arg15His) results in a non-conservative amino acid change located in the N-terminal domain (IPR032437) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.9e-05 in 242622 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.44G>A in individuals affected with Bloom Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One other clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV001022591	SCV001184345	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-11	criteria provided, single submitter	clinical testing	The p.R15H variant (also known as c.44G>A), located in coding exon 1 of the BLM gene, results from a G to A substitution at nucleotide position 44. The arginine at codon 15 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV002464199	SCV002010749	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV002464199	SCV002759102	uncertain significance	not provided	2022-06-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Natera, Inc.	RCV000463869	SCV002089881	uncertain significance	Bloom syndrome	2018-10-09	no assertion criteria provided	clinical testing