ClinVar Miner

Submissions for variant NM_020533.3(MCOLN1):c.1406A>G (p.Asn469Ser)

gnomAD frequency: 0.00001  dbSNP: rs797044818
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000192302 SCV001363133 likely pathogenic Mucolipidosis type IV 2022-08-29 criteria provided, single submitter clinical testing Variant summary: MCOLN1 c.1406A>G (p.Asn469Ser, legacy name: g.9107A>G) results in a conservative amino acid change located in the polycystin cation channel, PKD1/PKD2 domain (IPR013122) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a cryptic exonic 3' acceptor site, which if used, would result in an in-frame deletion expected to disrupt the pore architecture of the channel (e.g. Zhang_2017). However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250910 control chromosomes (gnomAD). c.1406A>G has been reported in the literature as a biallelic genotype in at least two individuals affected with Mucolipidosis Type 4 (e.g. Sun_2000). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters, including a reputable database, GeneReviews, have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneReviews RCV000192302 SCV000243824 not provided Mucolipidosis type IV no assertion provided literature only Base pair transition creates a new preferred splice acceptor site that results in a frameshift. Causes atypical MLIV, in which affected persons walk independently and have better communicative skills.
Natera, Inc. RCV000192302 SCV002091408 likely pathogenic Mucolipidosis type IV 2017-09-25 no assertion criteria provided clinical testing

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