ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.4140T>G (p.Ser1380Arg) (rs747834576)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000414956 SCV000795490 uncertain significance Bloom syndrome 2017-11-08 criteria provided, single submitter clinical testing
Invitae RCV000414956 SCV000933126 uncertain significance Bloom syndrome 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 1380 of the BLM protein (p.Ser1380Arg). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and arginine. This variant is present in population databases (rs747834576, ExAC 0.001%). This variant has been observed in trans with a pathogenic BLM variant in an individual with multiple congenital anomalies who also had a second molecular cause of disease (PMID: 27959697). ClinVar contains an entry for this variant (Variation ID: 374316). 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, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV001021941 SCV001183619 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-22 criteria provided, single submitter clinical testing Insufficient evidence
Baylor Genetics RCV000414956 SCV000328795 uncertain significance Bloom syndrome 2016-05-01 no assertion criteria provided clinical testing Our laboratory reported two molecular diagnoses in GLI2 (NM_005270.4:c.3261dupC) and BLM (NM_000057.2:c.1544del; NM_000057.2:c.4140T>G; in trans) in an individual with failure to thrive, motor and speech delay, intellectual disability, abnormal movements, dysmorphic features, microcephaly, structural brain abnormalities, eye anomalies, congenital heart disease, kidney abnormalities, skeletal abnormalities, limb malformation, delayed bone age, genital anomalies, hypopituitarism, behavior problems, and holoprosencephaly.

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