ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.736+5G>A (rs750518463)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000441406 SCV000524666 uncertain significance not provided 2016-12-28 criteria provided, single submitter clinical testing The c.736+5 G>A variant of uncertain significance in the CBS gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. In silico splicing algorithms predict this variant destroys the natural splice donor site in intron 8 of the CBS gene. However, this substitution occurs at a nucleotide position that is not conserved, where adenine is the native nucleotide in multiple species. Thus, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined. Other splice site variants in the CBS gene have been reported in HGMD in association with homocystinuria (Stenson et al., 2014). Moreover, the c.736+5 G>A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, and it was not observed with any significant frequency in the Exome Aggregation Consortium (ExAC), indicating it is not a common benign variant in these populations.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. This result cannot be interpreted for diagnosis or used for family member screening at this time.
Ambry Genetics RCV000618579 SCV000738493 uncertain significance Cardiovascular phenotype 2017-10-23 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV001239517 SCV001412393 uncertain significance Classic homocystinuria 2019-02-18 criteria provided, single submitter clinical testing This sequence change falls in intron 8 of the CBS gene. It does not directly change the encoded amino acid sequence of the CBS protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs750518463, ExAC 0.02%). This variant has not been reported in the literature in individuals with CBS-related conditions. ClinVar contains an entry for this variant (Variation ID: 384021). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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.

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