NM_152424.4(AMER1):c.1057C>T (p.Arg353Ter) AND Osteopathia striata with cranial sclerosis

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jan 5, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000011453.13

Allele description [Variation Report for NM_152424.4(AMER1):c.1057C>T (p.Arg353Ter)]

NM_152424.4(AMER1):c.1057C>T (p.Arg353Ter)

Gene:

AMER1:APC membrane recruitment protein 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq11.2

Genomic location:

Preferred name:

NM_152424.4(AMER1):c.1057C>T (p.Arg353Ter)

HGVS:

NC_000023.11:g.64192230G>A
NG_021345.1:g.18515C>T
NM_152424.4:c.1057C>TMANE SELECT
NP_689637.3:p.Arg353Ter
LRG_1259t1:c.1057C>T
LRG_1259:g.18515C>T
LRG_1259p1:p.Arg353Ter
NC_000023.10:g.63412110G>A
NM_152424.3:c.1057C>T
p.Arg353X

Protein change:

R353*; ARG353TER

Links:

OMIM: 300647.0004; dbSNP: rs137852216

NCBI 1000 Genomes Browser:

rs137852216

Molecular consequence:

NM_152424.4:c.1057C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Osteopathia striata with cranial sclerosis (OSCS)
Synonyms:: HYPEROSTOSIS GENERALISATA WITH STRIATIONS; Osteopathia striata cranial sclerosis
Identifiers:: MONDO: MONDO:0010310; MedGen: C0432268; Orphanet: 2780; OMIM: 300373

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000031685	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 2009)	unknown	literature only	PubMed (1) [See all records that cite this PMID]
SCV000967591	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Apr 21, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19079258, 22716240, 27369646, 24033266
SCV001426759	Women's and Children's Health, University of Otago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	de novo	provider interpretation	PubMed (1) [See all records that cite this PMID]
SCV002061240	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 5, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19079258, 22716240, 27369646, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	de novo	yes	1	not provided	not provided	1	not provided	provider interpretation
not provided	unknown	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Germline mutations in WTX cause a sclerosing skeletal dysplasia but do not predispose to tumorigenesis.

Jenkins ZA, van Kogelenberg M, Morgan T, Jeffs A, Fukuzawa R, Pearl E, Thaller C, Hing AV, Porteous ME, Garcia-Miñaur S, Bohring A, Lacombe D, Stewart F, Fiskerstrand T, Bindoff L, Berland S, Adès LC, Tchan M, David A, Wilson LC, Hennekam RC, Donnai D, et al.

Nat Genet. 2009 Jan;41(1):95-100. doi: 10.1038/ng.270. Epub 2008 Dec 14.

PubMed [citation]

PMID:: 19079258

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000031685.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 2 unrelated females with osteopathia striata with cranial sclerosis (OSCS; 300373), Jenkins et al. (2009) identified a 1057C-T transition in the WTX gene, resulting in an arg353-to-stop (R353X) substitution. In both cases this was a de novo occurrence. This mutation had been reported as a somatic mutation in Wilms tumor (see 194070); however, neither of these patients had any history of cancer.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000967591.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

Description

The p.Arg353X variant in AMER1 has been reported in 4 individuals with osteopath ia striata-cranial sclerosis (OSCS), occurring de novo in 2 individuals and segr egating with disease in an affected family member in 2 families (Jenkins 2009, Z icari 2012, Fradin 2017). The variant was not reported in large population datab ases, but has been reported in the COSMIC database as a somatic variant that was detected in two colorectal adenocarcinoma samples (Mutation ID: COSM6495573; ht tp://cancer.sanger.ac.uk/cosmic/). However, germline p.Arg353X variants in OSCS patients have not been associated with an increased risk of cancer (Jenkins 2009 , Zicari 2012, Fradin 2017). This nonsense variant leads to a premature terminat ion codon at position 353, and is predicted to result in a truncated protein (Je nkens 2009). Loss of function of AMER1 due to truncating germline variants is an established disease mechanism for OSCS. In summary, this variant meets criteria to be classified as pathogenic for OSCS in an X-linked dominant manner. ACMG/AM P Criteria applied: PM6_Strong; PM2; PM4; PS4_Moderate; PP4.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		1	not provided	1	not provided

From Women's and Children's Health, University of Otago, SCV001426759.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	provider interpretation	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	1	not provided	not provided		1	not provided	not provided	not provided

From DASA, SCV002061240.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

Description

The c.1057C>T;p.(Arg353*) variant creates a premature translational stop signal in the AMER1 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant(ClinVar ID: 10707; OMIM: 300647.0004; PMID: 19079258; 22716240; 27369646) - PS4. This variant is not present in population databases (rs137852216, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 19079258, 27369646) - PM6. The variant co-segregated with disease in multiple affected family members (PMID: 22716240) - PP1. In summary, the currently available evidence indicates that the variant is pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Aug 11, 2024

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