PS4_MOD, PP1, PS3, PM3
ClinVar Genomic variation as it relates to human health
NM_001395891.1(CLASP1):c.196-567G>A
Germline
Classification
Help
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.
(14)
Help
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
14
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001395891.1(CLASP1):c.196-567G>A
Variation ID: 218083 Accession: VCV000218083.38
- Type and length
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single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q14.2 2: 121530892 (GRCh38) [ NCBI UCSC ] 2: 122288468 (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, 2017 Nov 17, 2024 Nov 11, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001395891.1:c.196-567G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001142273.2:c.196-567G>A intron variant NM_001142274.2:c.196-567G>A intron variant NM_001207051.2:c.196-567G>A intron variant NM_001378003.1:c.196-567G>A intron variant NM_001378004.1:c.196-567G>A intron variant NM_001378005.1:c.196-567G>A intron variant NM_015282.2:c.196-567G>A NM_015282.3:c.196-567G>A intron variant NR_023343.3:n.13C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NC_000002.12:g.121530892C>T NC_000002.11:g.122288468C>T NG_029832.1:g.5013C>T LRG_1202:g.5013C>T LRG_1202t1:n.13C>T - Protein change
- -
- Other names
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13C-T
- Canonical SPDI
- NC_000002.12:121530891:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe 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.
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0.00020 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00047
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Trans-Omics for Precision Medicine (TOPMed) 0.00037
The Genome Aggregation Database (gnomAD) 0.00038
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| CLASP1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
65 | 334 | |
| RNU4ATAC | - | - |
GRCh38 GRCh37 |
1 | 267 | |
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. |
|---|---|---|---|---|
| Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Nov 11, 2024 | RCV000202315.15 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jun 1, 2024 | RCV000788934.28 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 23, 2022 | RCV002478721.3 | |
|
CLASP1-related disorder
|
Pathogenic (1) |
no assertion criteria provided
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Aug 25, 2024 | RCV004754354.1 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Oct 02, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Roifman syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
paternal,
maternal
|
Undiagnosed Diseases Network, NIH
Accession: SCV000837725.2
First in ClinVar: Oct 10, 2018 Last updated: May 09, 2020 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Ventriculomegaly (present) , Upper airway obstruction (present) , Small for gestational age (present) , Recurrent upper and lower respiratory tract infections (present) , Posteriorly rotated … (more)
Ventriculomegaly (present) , Upper airway obstruction (present) , Small for gestational age (present) , Recurrent upper and lower respiratory tract infections (present) , Posteriorly rotated ears (present) , Poor suck (present) , Muscular hypotonia (present) , Microcephaly (present) , Low-set ears (present) , Intrauterine growth retardation (present) , Global developmental delay (present) , Generalized tonic-clonic seizures (present) , Gastroparesis (present) , Gastroesophageal reflux (present) , Gastritis (present) , Feeding difficulties (present) , Failure to thrive (present) , Episodic vomiting (present) , Birth length less than 3rd percentile (present) , Asthma (present) , Abnormality of the cerebral white matter (present) , Abnormal ciliary motility (present) (less)
Age: 0-9 years
Sex: male
Ethnicity/Population group: White
Tissue: blood
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Ventriculomegaly (present) , Small for gestational age (present) , Shortening of all phalanges of fingers (present) , Short toe (present) , Short stature (present) , … (more)
Ventriculomegaly (present) , Small for gestational age (present) , Shortening of all phalanges of fingers (present) , Short toe (present) , Short stature (present) , Short dental roots (present) , Scoliosis (present) , Premature birth (present) , Long palpebral fissure (present) , Intellectual disability (present) , Hypomagnesemia (present) , Partial congenital absence of teeth (present) , Fused labia minora (present) , Finger syndactyly (present) , Dry skin (present) , Calcified placenta (present) , Caesarian section (present) , Asthma (present) , Arrhythmia (present) , Abnormal delivery (present) (less)
Age: 10-19 years
Sex: female
Ethnicity/Population group: Hispanic
Tissue: blood
Testing laboratory: Baylor Genetics
Date variant was reported to submitter: 2019-10-02
Testing laboratory interpretation: Pathogenic
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Pathogenic
(Feb 18, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000928232.1
First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019
Comment:
Patient analyzed with Primary Immunodeficiency Panel
|
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Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446768.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Rod-cone dystrophy (present) , Atopic eczema (present) , Decreased circulating antibody concentration (present) , Short stature (present) , Hearing impairment (present)
Sex: male
|
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Pathogenic
(Mar 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Osteodysplastic primordial dwarfism, type 1
Lowry-Wood syndrome Roifman syndrome
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002794997.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
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Pathogenic
(Apr 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
paternal
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV004026341.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Comment:
PS4_MOD, PP1, PS3, PM3
|
|
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Pathogenic
(Jan 19, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002222473.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This variant occurs in the RNU4ATAC gene, which encodes an RNA molecule that does not result in a protein product. This variant is present in … (more)
This variant occurs in the RNU4ATAC gene, which encodes an RNA molecule that does not result in a protein product. This variant is present in population databases (rs559979281, gnomAD 0.06%). This variant has been observed in individual(s) with Roifman syndrome (PMID: 26522830, 28623346, 30455926, 32109076). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218083). Functional studies have shown that this variant disrupts ncRNA function (PMID: 32628740). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 08, 2024)
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criteria provided, single submitter
Method: clinical testing
|
Roifman syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005039932.2
First in ClinVar: May 07, 2024 Last updated: Jul 07, 2024 |
Comment:
Variant summary: RNU4ATAC n.13C>T alters a conserved nucleotide in the non-coding RNA. The variant allele was found at a frequency of 0.00035 in 129764 control … (more)
Variant summary: RNU4ATAC n.13C>T alters a conserved nucleotide in the non-coding RNA. The variant allele was found at a frequency of 0.00035 in 129764 control chromosomes. n.13C>T has been reported in the literature in multiple individuals affected with Roifman Syndrome (example Merico_2015, Maddirevula_ 2018, Bhattad_2023). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 37898571, 29620724, 26522830). ClinVar contains an entry for this variant (Variation ID: 218083). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Sep 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Roifman syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005086388.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with microcephalic osteodysplastic primordial dwarfism, type I (MIM#210710), Roifman syndrome (MIM#616651), and Lowry-Wood syndrome (MIM#226960). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0217 - Non-coding variant with known effect. Transfected cells were proven to demonstrate significantly reduced splicing efficiencies (PMID: 32628740). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (62 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the same position, is present in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0600 - Variant is located in the functionally important stem II region of the small nuclear RNA (PMID: 32628740). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and observed in compound heterozygous individuals with Roifman syndrome (ClinVar, PMID: 32628740). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Jun 01, 2024)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001746666.20
First in ClinVar: Jul 10, 2021 Last updated: Oct 20, 2024 |
Comment:
RNU4ATAC: PM3:Very Strong, PM2, PP1:Moderate, PS3:Supporting
Number of individuals with the variant: 7
|
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Pathogenic
(Nov 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Roifman syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV005397132.1
First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024 |
Clinical Features:
Failure to thrive (present) , Decreased body weight (present) , Microcephaly (present) , Feeding difficulties (present)
Sex: female
|
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Pathogenic
(Nov 02, 2015)
|
no assertion criteria provided
Method: literature only
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ROIFMAN SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000257314.2
First in ClinVar: Nov 22, 2015 Last updated: May 01, 2017 |
Comment on evidence:
In 2 brothers of Irish descent with Roifman syndrome (RFMN; 616651), previously reported by Roifman (1999), Merico et al. (2015) identified compound heterozygosity for a … (more)
In 2 brothers of Irish descent with Roifman syndrome (RFMN; 616651), previously reported by Roifman (1999), Merico et al. (2015) identified compound heterozygosity for a 13C-T transition and a 37G-A transition in the RNU4ATAC gene (GenBank NR_023343), both of which involve highly conserved nucleotides in stem II region and the 5-prime stem-loop critical region, respectively. In an Italian man with Roifman syndrome, the 13C-T variant was present in compound heterozygosity with a 48G-A transition (601428.0013) that also involves a highly conserved nucleotide in the stem II region. The unaffected parents in both families were each heterozygous for 1 of the variants. None of the variants was found in the 1000 Genomes Project or Complete Genomics databases, but the 13C-T variant was present at a frequency of 0.0008 in the Wellderly study database. (less)
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Likely pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Roifman syndrome
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001161807.1
First in ClinVar: Feb 27, 2020 Last updated: Feb 27, 2020 |
Number of individuals with the variant: 1
Sex: male
|
|
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Pathogenic
(Aug 25, 2024)
|
no assertion criteria provided
Method: clinical testing
|
CLASP1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004116182.2
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The CLASP1 c.196-567G>A variant is predicted to interfere with splicing. This variant has been reported in the compound heterozygous state with other noncoding variants in … (more)
The CLASP1 c.196-567G>A variant is predicted to interfere with splicing. This variant has been reported in the compound heterozygous state with other noncoding variants in RNU4ATAC in patients with Roifman syndrome (Merico et al. 2015. PubMed ID: 26522830; Bogaert et al. 2017. PubMed ID: 28623346; Hallermayr et al. 2018. PubMed ID: 30455926; Wang et al. 2020. PubMed ID: 32109076). Functional studies showed that this variant disrupts ncRNA function (Benoit-Pilven et al. 2020. PubMed ID: 32628740). This variant is reported in 0.059% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
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Uncertain significance
(Nov 22, 2022)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
Roifman syndrome
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807779.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: PS3 supporting, PM3 moderated
Number of individuals with the variant: 1
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
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| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
This variant occurs in the RNU4ATAC gene, which encodes an RNA molecule that does not result in a protein product. This variant is present in population databases (rs559979281, gnomAD 0.06%). This variant has been observed in individual(s) with Roifman syndrome (PMID: 26522830, 28623346, 30455926, 32109076). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218083). Functional studies have shown that this variant disrupts ncRNA function (PMID: 32628740). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: RNU4ATAC n.13C>T alters a conserved nucleotide in the non-coding RNA. The variant allele was found at a frequency of 0.00035 in 129764 control chromosomes. n.13C>T has been reported in the literature in multiple individuals affected with Roifman Syndrome (example Merico_2015, Maddirevula_ 2018, Bhattad_2023). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 37898571, 29620724, 26522830). ClinVar contains an entry for this variant (Variation ID: 218083). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with microcephalic osteodysplastic primordial dwarfism, type I (MIM#210710), Roifman syndrome (MIM#616651), and Lowry-Wood syndrome (MIM#226960). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0217 - Non-coding variant with known effect. Transfected cells were proven to demonstrate significantly reduced splicing efficiencies (PMID: 32628740). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (62 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the same position, is present in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0600 - Variant is located in the functionally important stem II region of the small nuclear RNA (PMID: 32628740). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and observed in compound heterozygous individuals with Roifman syndrome (ClinVar, PMID: 32628740). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
RNU4ATAC: PM3:Very Strong, PM2, PP1:Moderate, PS3:Supporting
Comment:
The CLASP1 c.196-567G>A variant is predicted to interfere with splicing. This variant has been reported in the compound heterozygous state with other noncoding variants in RNU4ATAC in patients with Roifman syndrome (Merico et al. 2015. PubMed ID: 26522830; Bogaert et al. 2017. PubMed ID: 28623346; Hallermayr et al. 2018. PubMed ID: 30455926; Wang et al. 2020. PubMed ID: 32109076). Functional studies showed that this variant disrupts ncRNA function (Benoit-Pilven et al. 2020. PubMed ID: 32628740). This variant is reported in 0.059% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Comment:
ACMG classification criteria: PS3 supporting, PM3 moderated
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:
PS4_MOD, PP1, PS3, PM3
Comment:
This variant occurs in the RNU4ATAC gene, which encodes an RNA molecule that does not result in a protein product. This variant is present in population databases (rs559979281, gnomAD 0.06%). This variant has been observed in individual(s) with Roifman syndrome (PMID: 26522830, 28623346, 30455926, 32109076). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218083). Functional studies have shown that this variant disrupts ncRNA function (PMID: 32628740). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: RNU4ATAC n.13C>T alters a conserved nucleotide in the non-coding RNA. The variant allele was found at a frequency of 0.00035 in 129764 control chromosomes. n.13C>T has been reported in the literature in multiple individuals affected with Roifman Syndrome (example Merico_2015, Maddirevula_ 2018, Bhattad_2023). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 37898571, 29620724, 26522830). ClinVar contains an entry for this variant (Variation ID: 218083). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with microcephalic osteodysplastic primordial dwarfism, type I (MIM#210710), Roifman syndrome (MIM#616651), and Lowry-Wood syndrome (MIM#226960). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0217 - Non-coding variant with known effect. Transfected cells were proven to demonstrate significantly reduced splicing efficiencies (PMID: 32628740). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (62 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the same position, is present in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0600 - Variant is located in the functionally important stem II region of the small nuclear RNA (PMID: 32628740). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and observed in compound heterozygous individuals with Roifman syndrome (ClinVar, PMID: 32628740). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
RNU4ATAC: PM3:Very Strong, PM2, PP1:Moderate, PS3:Supporting
Comment:
The CLASP1 c.196-567G>A variant is predicted to interfere with splicing. This variant has been reported in the compound heterozygous state with other noncoding variants in RNU4ATAC in patients with Roifman syndrome (Merico et al. 2015. PubMed ID: 26522830; Bogaert et al. 2017. PubMed ID: 28623346; Hallermayr et al. 2018. PubMed ID: 30455926; Wang et al. 2020. PubMed ID: 32109076). Functional studies showed that this variant disrupts ncRNA function (Benoit-Pilven et al. 2020. PubMed ID: 32628740). This variant is reported in 0.059% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Comment:
ACMG classification criteria: PS3 supporting, PM3 moderated
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Profile of 208 patients with inborn errors of immunity at a tertiary care center in South India. | Bhattad S | Clinical and experimental medicine | 2023 | PMID: 37898571 |
| Clinical interpretation of variants identified in RNU4ATAC, a non-coding spliceosomal gene. | Benoit-Pilven C | PloS one | 2020 | PMID: 32628740 |
| Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
| Highly Enantioselective Ruthenium-Catalyzed Cascade Double Reduction Strategy: Construction of Structurally Diverse Julolidines and Their Analogues. | Wang LR | Organic letters | 2020 | PMID: 32109076 |
| Extending the critical regions for mutations in the non-coding gene RNU4ATAC in another patient with Roifman Syndrome. | Hallermayr A | Clinical case reports | 2018 | PMID: 30455926 |
| Expanding the phenome and variome of skeletal dysplasia. | Maddirevula S | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29620724 |
| Early-onset primary antibody deficiency resembling common variable immunodeficiency challenges the diagnosis of Wiedeman-Steiner and Roifman syndromes. | Bogaert DJ | Scientific reports | 2017 | PMID: 28623346 |
| Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing. | Merico D | Nature communications | 2015 | PMID: 26522830 |
| Antibody deficiency, growth retardation, spondyloepiphyseal dysplasia and retinal dystrophy: a novel syndrome. | Roifman CM | Clinical genetics | 1999 | PMID: 10189087 |
Text-mined citations for rs559979281 ...
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Record last updated Nov 25, 2024
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