ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.1544del (p.Asn515fs) (rs367543043)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000415444 SCV000916677 pathogenic Bloom syndrome 2017-10-30 criteria provided, single submitter clinical testing Variant summary: The BLM c.1544delA (p.Asn515MetfsX16) variant results in a premature termination codon, predicted to cause a truncated or absent BLM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.2824-1077_3019+310del1583, p.V942fs; c.2207_2212del6insTAGATTC, p.Tyr736fsX5; c.772_773delCT, p.Leu258fsX7). One in silico tool predicts a damaging outcome for this variant.This variant is absent in 245606 control chromosomes (gnomAD). A different variant (BLM c.1544_1545dupA) leading to the same protein change, p.Asn515MetfsX16, was reported in multiple Bloom Syndrome patients (German_2007). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000415444 SCV001208097 pathogenic Bloom syndrome 2019-10-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn515Metfs*16) in the BLM gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in combination with another 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: 374315). Loss-of-function variants in BLM are known to be pathogenic (PMID: 17407155). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000415444 SCV000328794 pathogenic 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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