ClinVar Miner

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

gnomAD frequency: 0.00224  dbSNP: rs140213840
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000005761 SCV000915493 uncertain significance Amelogenesis imperfecta hypomaturation type 2A2 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.
CeGaT Center for Human Genetics Tuebingen RCV001240725 SCV002497162 pathogenic not provided 2023-09-01 criteria provided, single submitter clinical testing MMP20: PVS1, PM3, PM2:Supporting
GeneDx RCV001240725 SCV002526509 pathogenic not provided 2022-06-15 criteria provided, single submitter clinical testing Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31980526, 25525159, 15744043, 22243262, 28659819, 26502894, 21597265, 16246936, 26124219, 16838342, 32495503, 31589614, 33600052)
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000005761 SCV002762764 pathogenic Amelogenesis imperfecta hypomaturation type 2A2 2022-11-09 criteria provided, single submitter research ACMG codes:PVS1_VeryStrong, PM2_Supporting, PM3_Strong
PreventionGenetics, part of Exact Sciences RCV003415660 SCV004106338 pathogenic MMP20-related condition 2024-01-03 criteria provided, single submitter clinical testing The MMP20 c.954-2A>T variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been previously reported in the homozygous or compound heterozygous state in several individuals with autosomal recessive amelogenesis imperfecta (Kim et al. 2005. PubMed ID: 15744043; Chan et al. 2011. PubMed ID: 22243262; Wright et al. 2011. PubMed ID: 21597265; Gasse et al. 2013. PubMed ID: 23625376; Prasad et al. 2016. PubMed ID: 26502894; Wang et al. 2020. PubMed ID: 32495503). It has also been identified in a genome sequencing cohort and interpreted as likely pathogenic (Hou et al. 2020. PubMed ID: 31980526). This variant is reported in 0.19% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice acceptor site in MMP20 are expected to be pathogenic. This variant is interpreted as pathogenic.
OMIM RCV000005761 SCV000025943 pathogenic Amelogenesis imperfecta hypomaturation type 2A2 2005-03-01 no assertion criteria provided literature only

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