Submissions for variant NM_000057.4(BLM):c.4126A>G (p.Ile1376Val)

gnomAD frequency: 0.00006  dbSNP: rs587779892

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115319	SCV000149228	uncertain significance	not provided	2022-08-17	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
Invitae	RCV000553041	SCV000623333	uncertain significance	Bloom syndrome	2022-09-23	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1376 of the BLM protein (p.Ile1376Val). This variant is present in population databases (rs587779892, gnomAD 0.0009%). 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: 127511). 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 valine 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	RCV001021918	SCV001183594	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-04	criteria provided, single submitter	clinical testing	The p.I1376V variant (also known as c.4126A>G), located in coding exon 21 of the BLM gene, results from an A to G substitution at nucleotide position 4126. The isoleucine at codon 1376 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and valine is the reference amino acid in other 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.
Illumina Laboratory Services, Illumina	RCV000553041	SCV001279114	uncertain significance	Bloom syndrome	2018-03-02	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000115319	SCV002010564	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000553041	SCV002090661	uncertain significance	Bloom syndrome	2018-12-22	no assertion criteria provided	clinical testing