VCV000031210.11 - ClinVar

NM_001374828.1(ARID1B):c.3673C>T (p.Arg1225Ter)

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.

(7)

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_001374828.1(ARID1B):c.3673C>T (p.Arg1225Ter)

Variation ID: 31210 Accession: VCV000031210.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6q25.3 6: 157181137 (GRCh38) [ NCBI UCSC ] 6: 157502271 (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	May 1, 2016	Feb 14, 2024	Oct 27, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001374828.1:c.3673C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001361757.1:p.Arg1225Ter	nonsense
NM_001363725.2:c.1174C>T	NP_001350654.1:p.Arg392Ter	nonsense
NM_001371656.1:c.3553C>T	NP_001358585.1:p.Arg1185Ter	nonsense
NM_001374820.1:c.3553C>T	NP_001361749.1:p.Arg1185Ter	nonsense
NM_017519.3:c.3514C>T	NP_059989.3:p.Arg1172Ter	nonsense
NM_020732.3:c.3304C>T	NP_065783.3:p.Arg1102Ter	nonsense
NC_000006.12:g.157181137C>T
NC_000006.11:g.157502271C>T
NG_066624.1:g.410112C>T

... more HGVS ... less HGVS

Protein change

R1102*, R392*, R1172*, R1185*, R1225*

Other names

Canonical SPDI

NC_000006.12:157181136:C:T

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: CA129764 OMIM: 614556.0003 dbSNP: rs387907141 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.
ARID1B		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1899	2251

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.
Coffin-Siris syndrome 1	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Aug 18, 2021	RCV000024209.7
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 27, 2022	RCV000254764.5
ARID1B-related BAFopathy	Pathogenic (1)	criteria provided, single submitter	Jun 10, 2021	RCV001533118.1

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 (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Coffin-Siris syndrome 1 Affected status: yes Allele origin: unknown	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn Accession: SCV000999329.1 First in ClinVar: Nov 30, 2019 Last updated: Nov 30, 2019	Number of individuals with the variant: 1 Clinical Features: Delayed speech and language development (present) , Hypothyroidism (present) , Hearing impairment (present) , Downslanted palpebral fissures (present) , Congenital megaureter (present) , Clinodactyly of … (more) Delayed speech and language development (present) , Hypothyroidism (present) , Hearing impairment (present) , Downslanted palpebral fissures (present) , Congenital megaureter (present) , Clinodactyly of the 5th finger (present) , Cleft palate (present) , Brachycephaly (present) , Abnormality of the pinna (present) , Low anterior hairline (present) , Low-set, posteriorly rotated ears (present) , Microdontia (present) , Muscular hypotonia (present) , Myopia (present) , Wide mouth (present) , Widely spaced teeth (present) , Seizures (present) , Sandal gap (present) , Severe global developmental delay (present) , Dry hair (present) , Hypoplastic fifth toenail (present) , Allergy (present) , Thin upper lip vermilion (present) (less)
Pathogenic (Jun 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ARID1B-related BAFopathy Affected status: yes Allele origin: de novo	Baylor Genetics Accession: SCV001748938.1 First in ClinVar: Jul 10, 2021 Last updated: Jul 10, 2021
Pathogenic (Jul 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Coffin-Siris syndrome 1 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002054277.1 First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022
Pathogenic (Aug 18, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Coffin-Siris syndrome 1 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002805720.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Dec 16, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000322097.8 First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023	Comment: Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Tsurusaki … (more) Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Tsurusaki et al. (2012) confirmed the nonsense mediated RNA decay using RT-PCR in lymhoblastoid cell line derived from the patient harboring this variant; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22405089, 31077186, 22426308, 30349098, 27112773, 32339967, 28191889) (less)
Pathogenic (Oct 27, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004294427.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 22405089‚ 25674384‚ 30349098 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 31210). This premature translational stop signal … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 31210). This premature translational stop signal has been observed in individual(s) with Coffin-Siris syndrome (PMID: 22405089). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1102*) in the ARID1B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ARID1B are known to be pathogenic (PMID: 25674384, 30349098). (less)
Pathogenic (Mar 18, 2012)	no assertion criteria provided Method: literature only	COFFIN-SIRIS SYNDROME 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000045500.3 First in ClinVar: Apr 04, 2013 Last updated: May 01, 2016	Publications: PubMed (2) PubMed: 22405089‚ 22426308 Comment on evidence: In a 12-year-old girl with Coffin-Siris syndrome-1 (CSS1; 135900), Hoyer et al. (2012) identified a de novo heterozygous 3304C-T transition in exon 12 of the … (more) In a 12-year-old girl with Coffin-Siris syndrome-1 (CSS1; 135900), Hoyer et al. (2012) identified a de novo heterozygous 3304C-T transition in exon 12 of the ARID1B gene, resulting in an arg1102-to-ter (R1102X) substitution. She had short stature, severe developmental delay, delayed walking, poor speech, and hypotonia. She also had 1 seizure, unilateral hearing loss, brachycephaly and low forehead, low-set, posteriorly rotated, and abnormal ears, downslanting palpebral fissures, thin upper lip, cleft palate, sandal gaps, myopia, and wide mouth, among other minor dysmorphisms. Tsurusaki et al. (2012) identified this mutation occurring de novo in a patient (Patient 23) with Coffin-Siris syndrome. (less)

Comment:

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Tsurusaki et al. (2012) confirmed the nonsense mediated RNA decay using RT-PCR in lymhoblastoid cell line derived from the patient harboring this variant; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22405089, 31077186, 22426308, 30349098, 27112773, 32339967, 28191889)

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 31210). This premature translational stop signal has been observed in individual(s) with Coffin-Siris syndrome (PMID: 22405089). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1102*) in the ARID1B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ARID1B are known to be pathogenic (PMID: 25674384, 30349098).

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
The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin-Siris syndrome.	van der Sluijs PJ	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 30349098
ARID1B-mediated disorders: Mutations and possible mechanisms.	Sim JC	Intractable & rare diseases research	2015	PMID: 25674384
Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome.	Tsurusaki Y	Nature genetics	2012	PMID: 22426308
Haploinsufficiency of ARID1B, a member of the SWI/SNF-a chromatin-remodeling complex, is a frequent cause of intellectual disability.	Hoyer J	American journal of human genetics	2012	PMID: 22405089

Text-mined citations for rs387907141 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001374828.1(ARID1B):c.3673C>T (p.Arg1225Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs387907141 ...