ClinVar Miner

Submissions for variant NM_000190.4(HMBS):c.655G>T (p.Ala219Ser)

gnomAD frequency: 0.00004  dbSNP: rs767103817
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000850508 SCV000992711 uncertain significance Acute intermittent porphyria criteria provided, single submitter clinical testing
GeneDx RCV001759639 SCV001996373 uncertain significance not provided 2020-02-03 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31216405)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003489938 SCV004241700 uncertain significance not specified 2023-12-27 criteria provided, single submitter clinical testing Variant summary: HMBS c.655G>T (p.Ala219Ser) results in a conservative amino acid change located in the Porphobilinogen deaminase, N-terminal domain (IPR022417) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251280 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.655G>T has been reported in the literature in at-least one individual who had diagnostic exome sequencing analysis performed (example: Liu_2019). This report does not provide unequivocal conclusions about association of the variant with Acute Intermittent Porphyria. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31216405). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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