VCV000010894.8 - ClinVar

NM_012280.4(FTSJ1):c.655G>A (p.Asp219Asn)

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.

(3)

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

No data submitted for oncogenicity

Variant Details

Identifiers

NM_012280.4(FTSJ1):c.655G>A (p.Asp219Asn)

Variation ID: 10894 Accession: VCV000010894.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xp11.23 X: 48481715 (GRCh38) [ NCBI UCSC ] X: 48340103 (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	Apr 4, 2013	Nov 11, 2023	May 4, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_012280.4:c.655G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_036412.1:p.Asp219Asn	missense
NM_001282157.1:c.244G>A	NP_001269086.1:p.Asp82Asn	missense
NM_012280.2:c.655G>A
NM_012280.3:c.655G>A
NM_177434.1:c.655G>A	NP_803183.1:p.Asp219Asn	missense
NM_177439.3:c.655G>A	NP_803188.1:p.Asp219Asn	missense
NC_000023.11:g.48481715G>A
NC_000023.10:g.48340103G>A
NG_008879.1:g.10555G>A

... more HGVS ... less HGVS

Protein change

D219N, D82N

Other names

EX9DEL

Canonical SPDI

NC_000023.11:48481714:G:A

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

exon loss; Variation Ontology [ VariO:0381]

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

OMIM: 300499.0001 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.
FTSJ1		Some evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	82	247

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.
Intellectual disability, X-linked 9	Pathogenic (2)	criteria provided, single submitter	May 4, 2023	RCV000011641.8
not provided	Pathogenic (1)	criteria provided, single submitter	Feb 2, 2023	RCV003114186.3

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 (Feb 02, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003798915.2 First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023	Comment: Published cDNA studies show a deletion of exon 9, which is predicted to be in-frame (Freude et al. 2004); Not observed at significant frequency in … (more) Published cDNA studies show a deletion of exon 9, which is predicted to be in-frame (Freude et al. 2004); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10398246, 17221867, 15162322) (less)
Pathogenic (May 04, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Intellectual disability, X-linked 9 Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003933895.1 First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023	Publications: PubMed (2) PubMed: 15162322‚ 17221867 Comment: Variant summary: FTSJ1 c.655G>A (p.Asp219Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more) Variant summary: FTSJ1 c.655G>A (p.Asp219Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. In addition, this variant is located to the last nucleotide of exon 9, and therefore can affect splicing. Several computational tools predict a significant impact on normal splicing: three predict the variant weakens a 5' donor site, one predicts the variant abolishes a 5' splicing donor site. At least one publication reported experimental evidence confirming that this variant affects mRNA splicing, finding that the variant resulted in skipping of exon 9, with an in-frame deletion at the protein level (Freude_2004) that is predicted to disrupt the C-terminal part of the S-AdoMet-binding domain (Freude_2004). The variant was absent in 180681 control chromosomes. c.655G>A has been reported in the literature in several related individuals with Intellectual disability, X-linked 9, and the variant was shown to segregate with disease in these related individuals (e.g., Freude_2004, deBrouwer_2007). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 15162322, 17221867). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Aug 01, 2004)	no assertion criteria provided Method: literature only	INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED 9 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000031873.2 First in ClinVar: Apr 04, 2013 Last updated: Aug 24, 2021	Publications: PubMed (2) PubMed: 10398246‚ 15162322 Comment on evidence: In the family reported by Hamel et al. (1999) and designated MRX44 (XLID9; 309549), affected males had mild to moderate mental retardation. Freude et al. … (more) In the family reported by Hamel et al. (1999) and designated MRX44 (XLID9; 309549), affected males had mild to moderate mental retardation. Freude et al. (2004) found a single-nucleotide substitution (655G-A) at the last nucleotide of exon 9 in this family. Subsequent amplification of patient cDNA resulted in a fragment that was smaller than expected; direct sequencing of this specific product showed that exon 9 was absent. The absence introduced no frameshift in the FTSJ1 open reading frame, but the resulting FTSJ1 protein lacked 28 amino acids, which altered its structure and probably also its function. (less)

Comment:

Published cDNA studies show a deletion of exon 9, which is predicted to be in-frame (Freude et al. 2004); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10398246, 17221867, 15162322)

Comment:

Variant summary: FTSJ1 c.655G>A (p.Asp219Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. In addition, this variant is located to the last nucleotide of exon 9, and therefore can affect splicing. Several computational tools predict a significant impact on normal splicing: three predict the variant weakens a 5' donor site, one predicts the variant abolishes a 5' splicing donor site. At least one publication reported experimental evidence confirming that this variant affects mRNA splicing, finding that the variant resulted in skipping of exon 9, with an in-frame deletion at the protein level (Freude_2004) that is predicted to disrupt the C-terminal part of the S-AdoMet-binding domain (Freude_2004). The variant was absent in 180681 control chromosomes. c.655G>A has been reported in the literature in several related individuals with Intellectual disability, X-linked 9, and the variant was shown to segregate with disease in these related individuals (e.g., Freude_2004, deBrouwer_2007). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 15162322, 17221867). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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
Mutation frequencies of X-linked mental retardation genes in families from the EuroMRX consortium.	de Brouwer AP	Human mutation	2007	PMID: 17221867
Mutations in the FTSJ1 gene coding for a novel S-adenosylmethionine-binding protein cause nonsyndromic X-linked mental retardation.	Freude K	American journal of human genetics	2004	PMID: 15162322
Four families (MRX43, MRX44, MRX45, MRX52) with nonspecific X-linked mental retardation: clinical and psychometric data and results of linkage analysis.	Hamel BC	American journal of medical genetics	1999	PMID: 10398246

Text-mined citations for this variant ...

Record last updated Nov 11, 2023

ClinVar Genomic variation as it relates to human health

NM_012280.4(FTSJ1):c.655G>A (p.Asp219Asn)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...