ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.3970C>T (p.His1324Tyr)

gnomAD frequency: 0.00001  dbSNP: rs748943489
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000548110 SCV000623324 uncertain significance Bloom syndrome 2022-10-22 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 1324 of the BLM protein (p.His1324Tyr). This variant is present in population databases (rs748943489, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of Bloom syndrome (PMID: 17407155, 31159747). ClinVar contains an entry for this variant (Variation ID: 454145). 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. Experimental studies have shown that this missense change does not substantially affect BLM function (PMID: 17407155). 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.
GeneKor MSA RCV000708669 SCV000821906 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000708669 SCV001183184 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-01 criteria provided, single submitter clinical testing The p.H1324Y variant (also known as c.3970C>T), located in coding exon 20 of the BLM gene, results from a C to T substitution at nucleotide position 3970. The histidine at codon 1324 is replaced by tyrosine, an amino acid with similar properties. This variant has been identified in one person with Bloom Syndrome and functional studies have shown that it preserves normal BLM protein function in reducing the levels of sister-chromatid exchanges in patient-derived cells (German J et al. Hum. Mutat., 2007 Aug;28:743-53; Perreault-Micale C et al. Mol Genet Genomic Med, 2015 Jul;3:363-73). Another study determined that this variant (reported as c.3970C>T, p.H1324T) was not sensitive to the DNA damaging agent, hydroxyurea, similar to wildtype (Mirzaei H et al. Proc. Natl. Acad. Sci. U.S.A., 2012 Nov;109:19357-62). This variant was also reported as a variant of unknown signifcance in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). 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.
GeneDx RCV002281102 SCV002569600 uncertain significance not provided 2022-02-28 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; Observed in an individual undergoing genetic testing for hereditary cancer predisposition and in an individual with Bloom syndrome in published literature (German 2007, Tsaousis 2019); Published functional studies suggest no damaging effect: reduced levels of sister-chromatid exchanges (German 2007); This variant is associated with the following publications: (PMID: 26247052, 31159747, 17407155)
Natera, Inc. RCV000548110 SCV001456914 uncertain significance Bloom syndrome 2020-09-16 no assertion criteria provided clinical testing

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