ClinVar Miner

Submissions for variant NM_004771.4(MMP20):c.954-2A>T (rs140213840)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000005761 SCV000915493 uncertain significance Amelogenesis imperfecta, hypomaturation type, IIA2 2018-10-24 criteria provided, single submitter clinical testing The MMP20 c.954-2A>T variant occurs in a splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.954-2A>T variant has been reported in at least one study, in which it is found in a homozygous state in two members of the same family who were clinically affected with amelogenesis imperfecta (Kim et al. 2005). Unaffected family members carried this variant in heterozygous state. The variant was absent in 200 controls but is reported at a frequency of 0.019231 in the Puerto Rican population of the 1000 Genomes Project. The high allele frequency could be explained with the mild phenotype associated with the disease. Based on the potential impact of splice acceptor variants and clinical evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for amelogenesis imperfecta. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV001240725 SCV001413694 pathogenic not provided 2019-05-13 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 6 of the MMP20 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs140213840, ExAC 0.2%). This variant has been reported in several families and individuals affected with autosomal recessive pigmented hypomaturation amelogenesis imperfecta (PMID: 15744043, 22243262, 21597265, 26502894). ClinVar contains an entry for this variant (Variation ID: 5428). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MMP20 are known to be pathogenic (PMID: 18096894, 23625376). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000005761 SCV000025943 pathogenic Amelogenesis imperfecta, hypomaturation type, IIA2 2005-03-01 no assertion criteria provided literature only

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