Submissions for variant NM_152424.4(AMER1):c.1489C>T (p.Arg497Ter)

dbSNP: rs1930251154

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001069565	SCV001234741	likely pathogenic	not provided	2022-02-05	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 862773). This variant has not been reported in the literature in individuals affected with AMER1-related conditions. This variant is not present in population databases (gnomAD no frequency). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts the C-terminus of the AMER1 protein. Other variant(s) that disrupt this region (p.Leu546Phefs*34, p.Arg531*, p.Asp503Metfs*38) have been observed in individuals with AMER1-related conditions (PMID: 19079258, 22043478). This suggests that this may be a clinically significant region of the protein. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change creates a premature translational stop signal (p.Arg497*) in the AMER1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 639 amino acid(s) of the AMER1 protein.
3billion	RCV001775155	SCV002012055	pathogenic	Osteopathia striata with cranial sclerosis	2021-10-02	criteria provided, single submitter	clinical testing	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant has been reported as pathogenic (ClinVar ID: VCV000862773.2). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
GeneDx	RCV001069565	SCV002765212	likely pathogenic	not provided	2022-12-13	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation, as the last 639 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously reported as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 22043478, 19079258, 26071483)
Lifecell International Pvt. Ltd	RCV001775155	SCV003853261	pathogenic	Osteopathia striata with cranial sclerosis		criteria provided, single submitter	clinical testing	"A Nonsense variant c.1489C>T in Exon 2 of the AMER1 gene that results in premature truncation of the protein (p.Arg497*) was identified. The observed variant has a minor allele frequency of 0.00% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. The variant was found in ClinVar (Variant ID :862773) with a classification of Pathogenic/Likely Pathogenic and a review status of (2 star) criteria provided, multiple submitters, no conflicts. Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines."
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001775155	SCV003922295	likely pathogenic	Osteopathia striata with cranial sclerosis	2023-05-02	criteria provided, single submitter	curation	The hemizygous p.Arg497Ter variant in AMER1 was identified by our study in one individual with myopathy, seizures, and central hypoventilation. The p.Arg497Ter variant in AMER1 has been previously reported in 2 unrelated individuals with X-linked osteopathia striata with cranial sclerosis (ClinVar SCV002012055.1, SCV003853261.1). The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. This variant has also been reported in ClinVar (Variation ID: 862773) and has been interpreted as pathogenic by 3billion and LifeCell International Pvt. Ltd and as likely pathogenic by Invitae and GeneDx. This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 497. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the AMER1 gene is an established disease mechanism in X-linked osteopathia striata with cranial sclerosis. In summary, additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for X-linked osteopathia striata with cranial sclerosis. ACMG/AMP Criteria applied: PVS1_Strong, PS4_Supporting, PM2_Supporting (Richards 2015).