Submissions for variant NM_031889.3(ENAM):c.1259_1260insAG (p.Pro422fs)

gnomAD frequency: 0.00018  dbSNP: rs587776588

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001068458	SCV001233571	pathogenic	not provided	2022-07-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro422Valfs*27) in the ENAM gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 721 amino acid(s) of the ENAM protein. This variant is present in population databases (rs587776588, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with amelogenesis imperfecta (PMID: 14684688, 16246937, 17125728, 19329462, 20439930). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4238). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001068458	SCV002770400	likely pathogenic	not provided	2022-12-21	criteria provided, single submitter	clinical testing	Heterozygotes have been reported to have localized hypoplastic enamel pitting defects (Hart et al., 2003; Ozdemir et al., 2005; Pavlic et al., 2007); Frameshift variant predicted to result in protein truncation, as the last 721 amino acids are replaced with 26 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database and published literature (HGMD; Hart et al., 2003); This variant is associated with the following publications: (PMID: 34426522, 19329462, 28694781, 21597265, 31589614, 31069529, 20439930, 17125728, 31478359, 14684688, 16246937)
CeGaT Center for Human Genetics Tuebingen	RCV001068458	SCV004701554	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	ENAM: PM3:Strong, PVS1:Strong, PM2
OMIM	RCV000004460	SCV000024633	pathogenic	Amelogenesis imperfecta type 1C	2007-03-01	no assertion criteria provided	literature only
OMIM	RCV000144087	SCV000189167	pathogenic	Amelogenesis imperfecta - hypoplastic autosomal dominant - local	2007-03-01	no assertion criteria provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000004460	SCV000238460	likely pathogenic	Amelogenesis imperfecta type 1C	2014-07-31	no assertion criteria provided	research	The ENAM variant (c.1259_1260insAG,p.Pro422Valfs*27) identified in this patient is a frameshift variant considered to be likely pathogenic (Hart et al. 2003, PMID: 14684688 ; Wright et al. 2011, PMID: 21597265) and not associated with the autosomal dominant amelogenesis imperfecta type 1B (MIM:104500). Carriers of this condition have been reported to have localized enamel defects: pitted or grooved teeth, or small and discolored teeth that are prone to premature wearing.
PreventionGenetics, part of Exact Sciences	RCV003407274	SCV004116084	pathogenic	ENAM-related disorder	2024-01-17	no assertion criteria provided	clinical testing	The ENAM c.1259_1260insAG variant is predicted to result in a frameshift and premature protein termination (p.Pro422Valfs*27). This variant, also described as c.1258_1259insAG (p.P422fsX448) in the literature, has been reported in individuals with amelogenesis imperfecta (Hart et al. 2003. PubMed ID: 14684688; Pavlic et al. 2007. PubMed ID: 17125728; Wright et al. 2011. PubMed ID: 21597265; Zhang et al. 2019. PubMed ID: 31478359). It has been shown to be associated with phenotypic diversity, ranging from unaffected carrier parent (Family 2, Zhang et al. 2019. PubMed ID: 31478359), to localized hypoplastic enamel pitting as a dominant trait, and hypoplastic AI as a recessive trait (Family 1, Pavlic et al. 2007. PubMed ID: 17125728; Hart et al. 2003. PubMed ID: 14684688; Ozdemir et al. 2005. PubMed ID: 16246937). This variant is reported in 0.050% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in ENAM are expected to be pathogenic. This variant is interpreted as pathogenic.