VCV000010707.12 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(5)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

Oncogenicity

The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(1)

Stars represent the aggregate review status, or the level of review supporting the aggregate oncogenicity classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Likely oncogenic

criteria provided, single submitter

Variant Details

Identifiers

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

Variation ID: 10707 Accession: VCV000010707.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq11.2 X: 64192230 (GRCh38) [ NCBI UCSC ] X: 63412110 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 17, 2016	Mar 4, 2023	Jul 14, 2022
Somatic - Oncogenicity	Aug 11, 2024	Aug 11, 2024	Jul 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_152424.4:c.1057C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_689637.3:p.Arg353Ter	nonsense
NC_000023.11:g.64192230G>A
NC_000023.10:g.63412110G>A
NG_021345.1:g.18515C>T
LRG_1259:g.18515C>T
LRG_1259t1:c.1057C>T	LRG_1259p1:p.Arg353Ter

... more HGVS ... less HGVS

Protein change

R353*

Other names

Canonical SPDI

NC_000023.11:64192229:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA121147 OMIM: 300647.0004 dbSNP: rs137852216 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
AMER1		-	-	GRCh38 GRCh37	455	590

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Osteopathia striata with cranial sclerosis	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jan 5, 2022	RCV000011453.13
not provided	Pathogenic (1)	criteria provided, single submitter	Jul 14, 2022	RCV002266900.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Apr 21, 2018)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Osteopathia striata with cranial sclerosis (X-linked inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000967591.1 First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019	Publications: PubMed (3) PubMed: 19079258‚ 22716240‚ 27369646 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 1
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: provider interpretation	Osteopathia striata with cranial sclerosis Affected status: yes Allele origin: de novo	Women's and Children's Health, University of Otago Accession: SCV001426759.1 First in ClinVar: Aug 08, 2020 Last updated: Aug 08, 2020	Secondary finding: no
Pathogenic (Jan 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Osteopathia striata with cranial sclerosis Affected status: yes Allele origin: germline	DASA Accession: SCV002061240.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022	Publications: PubMed (3) PubMed: 19079258‚ 22716240‚ 27369646 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 1 Sex: female Geographic origin: Brazil
Pathogenic (Jul 14, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002549244.2 First in ClinVar: Jul 23, 2022 Last updated: Mar 04, 2023	Comment: Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 783 amino acids are lost, and other loss-of-function variants have been … (more) Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 783 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32879452, 22716240, 27369646, 33504798, 19079258) (less)
Pathogenic (Jan 01, 2009)	no assertion criteria provided Method: literature only	OSTEOPATHIA STRIATA WITH CRANIAL SCLEROSIS Affected status: not provided Allele origin: unknown	OMIM Accession: SCV000031685.4 First in ClinVar: Apr 04, 2013 Last updated: Mar 14, 2021	Publications: PubMed (1) PubMed: 19079258 Comment on evidence: 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 … (more) 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. (less)

Comment:

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.

Comment:

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.

Comment:

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 783 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32879452, 22716240, 27369646, 33504798, 19079258)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
First case of osteopathia striata with cranial sclerosis in an adult male with Klinefelter syndrome.	Fradin M	Joint bone spine	2017	PMID: 27369646
WTX R353X mutation in a family with osteopathia striata and cranial sclerosis (OS-CS): case report and literature review of the disease clinical, genetic and radiological features.	Zicari AM	Italian journal of pediatrics	2012	PMID: 22716240
Germline mutations in WTX cause a sclerosing skeletal dysplasia but do not predispose to tumorigenesis.	Jenkins ZA	Nature genetics	2009	PMID: 19079258

Conditions - Somatic

Tumor type Help The tumor type for this variant-condition (RCV) record in ClinVar.	Clinical impact (# of submissions) Help The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Oncogenicity Help The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the tumor type.	Variation/condition record Help The most recent date that a submitter evaluated this variant for the tumor type.
Neoplasm		Likely oncogenic criteria provided, single submitter	Jul 31, 2024	RCV004668713.1

Submissions - Somatic

Oncogenicity Help The submitted oncogenicity classification for each SCV record. (Last evaluated)	Review Status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Tumor type Help The tumor type for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.

Likely oncogenic

(Jul 31, 2024)

(ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022)

Method: clinical testing

Neoplasm

Affected status: unknown

Allele origin: somatic

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Accession: SCV005093900.1
First In ClinVar: Aug 11, 2024
Last updated: Aug 11, 2024

Comment:

Citations for somatic classification of this variant

There are no citations for somatic classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs137852216 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Aug 11, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Conditions - Somatic

Submissions - Somatic

Citations for somatic classification of this variant

Text-mined citations for rs137852216 ...