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

gnomAD frequency: 0.00224  dbSNP: rs140213840

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000005761	SCV000915493	pathogenic	Amelogenesis imperfecta hypomaturation type 2A2	2024-09-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	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
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000005761	SCV005086747	pathogenic	Amelogenesis imperfecta hypomaturation type 2A2	2024-09-20	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with amelogenesis imperfecta, type IIA2 (MIM#612529). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (234 heterozygotes, 1 homozygote). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, and as a VUS in one older entry. This variant has also been observed in homozygous and compound heterozygous individuals with amelogenesis imperfecta, including individuals compound heterozygous with c.103A>C (PMID: 15744043, 33600052, 37228816, 26502894). (SP) 1201- Heterozygous variant detected in trans with a second pathogenic heterozygous variant, NM_004771.3(MMP20):c.103A>C p.(Arg35=), in a recessive disease. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000005761	SCV000025943	pathogenic	Amelogenesis imperfecta hypomaturation type 2A2	2005-03-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003415660	SCV004106338	pathogenic	MMP20-related disorder	2024-09-03	no assertion criteria provided	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.