VCV000218082.24 - ClinVar

NM_001395891.1(CLASP1):c.196-570C>T

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.

(12)

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/Likely 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_001395891.1(CLASP1):c.196-570C>T

Variation ID: 218082 Accession: VCV000218082.24

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q14.2 2: 121530895 (GRCh38) [ NCBI UCSC ] 2: 122288471 (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	Oct 20, 2024	Jul 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001395891.1:c.196-570C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001142273.2:c.196-570C>T		intron variant
NM_001142274.2:c.196-570C>T		intron variant
NM_001207051.2:c.196-570C>T		intron variant
NM_001378003.1:c.196-570C>T		intron variant
NM_001378004.1:c.196-570C>T		intron variant
NM_001378005.1:c.196-570C>T		intron variant
NM_015282.3:c.196-570C>T		intron variant
NR_023343.3:n.16G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NC_000002.12:g.121530895G>A
NC_000002.11:g.122288471G>A
NG_029832.1:g.5016G>A
LRG_1202:g.5016G>A
LRG_1202t1:n.16G>A

... more HGVS ... less HGVS

Protein change

Other names

16G-A

Canonical SPDI

NC_000002.12:121530894: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.

Exome Aggregation Consortium (ExAC) 0.00019

Trans-Omics for Precision Medicine (TOPMed) 0.00022

Links

ClinGen: CA210442 OMIM: 601428.0010 dbSNP: rs750325275 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.
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.
Roifman syndrome	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Dec 8, 2022	RCV000202313.11
Intellectual disability Short stature	Pathogenic (1)	criteria provided, single submitter	May 24, 2019	RCV001263286.2
not provided	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jul 1, 2024	RCV001596985.19
Lowry-Wood syndrome Osteodysplastic primordial dwarfism, type 1 Roifman syndrome	Pathogenic (1)	criteria provided, single submitter	Mar 19, 2022	RCV002494514.2

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 (Nov 30, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001832293.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 Comment: Patient analyzed with Comprehensive Growth Disorders / Skeletal Dysplasias and Disorders Panel
Pathogenic (Jan 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Roifman syndrome (Autosomal recessive inheritance) Affected status: yes Allele origin: maternal	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV002523166.1 First in ClinVar: Jun 10, 2022 Last updated: Jun 10, 2022	Publications: PubMed (5) PubMed: 26522830‚ 28669401‚ 29263834‚ 29391254‚ 32595695 Number of individuals with the variant: 1 Clinical Features: Fetal growth restriction (present) , Small for gestational age (present) , Hyperbilirubinemia (present) , Hypertyrosinemia (present) , Feeding difficulties (present) , Abnormal circulating alpha-fetoprotein concentration … (more) Fetal growth restriction (present) , Small for gestational age (present) , Hyperbilirubinemia (present) , Hypertyrosinemia (present) , Feeding difficulties (present) , Abnormal circulating alpha-fetoprotein concentration (present) , Anteverted nares (present) , Proptosis (present) , Skin rash (present) , Global developmental delay (present) , Abnormal hair morphology (present) , Hypertyrosinemia (present) , Short stature (present) , Primary microcephaly (present) , Flat face (present) (less) Age: 0-9 years Sex: female
Pathogenic (Mar 19, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Osteodysplastic primordial dwarfism, type 1 Lowry-Wood syndrome Roifman syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002775399.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Dec 08, 2022)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Roifman syndrome (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV004045831.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Number of individuals with the variant: 1 Clinical Features: B lymphocytopenia (present) , Visual impairment (present) , Fetal growth restriction (present) , Hypoplasia of the corpus callosum (present) , Abnormal circulating immunoglobulin concentration (present) … (more) B lymphocytopenia (present) , Visual impairment (present) , Fetal growth restriction (present) , Hypoplasia of the corpus callosum (present) , Abnormal circulating immunoglobulin concentration (present) , Decreased response to growth hormone stimulation test (present) (less)
Pathogenic (Dec 06, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV004234930.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Likely pathogenic (Apr 04, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004809606.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024
Pathogenic (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004042081.11 First in ClinVar: Oct 14, 2023 Last updated: Oct 20, 2024	Comment: RNU4ATAC: PM3:Very Strong, PM2 Number of individuals with the variant: 2
Pathogenic (May 24, 2019)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Intellectual disability Short stature (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	New York Genome Center Study: CSER-NYCKidSeq Accession: SCV001441324.1 First in ClinVar: Nov 06, 2020 Last updated: Nov 06, 2020	Publications: PubMed (3) PubMed: 29391254‚ 29263834‚ 26522830 Comment: The NR_023343.1:n.16G>A a non coding transcript variant has been observed in the homozygous state or as a compound heterozygous, in trans with another disease-causing variant … (more) The NR_023343.1:n.16G>A a non coding transcript variant has been observed in the homozygous state or as a compound heterozygous, in trans with another disease-causing variant in association with autosomal recessive Roifman syndrome [MIM#616651] or autosomal recessivemicrocephalic osteodysplastic primordial dwarfism type 1 (MOPD1) [MIM#210710] [PMID: 29391254; PMID: 29263834; PMID:26522830]. The variant has 0.014% allele frequency in the gnomAD database (23 out of 161,196 heterozygous alleles) indicating this is a rare variant. Based on the available evidence, the variant n.16G>A is classified as Pathogenic (less) Secondary finding: no
Likely pathogenic (Feb 28, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Roifman syndrome Affected status: yes Allele origin: germline	Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital Accession: SCV001739476.1 First in ClinVar: Jul 07, 2021 Last updated: Jul 07, 2021	Number of individuals with the variant: 1 Age: 0-9 years Sex: female Ethnicity/Population group: East asia Geographic origin: China Testing laboratory: Liwei's Lab
Pathogenic (Oct 17, 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: SCV002229330.2 First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023	Publications: PubMed (6) PubMed: 26522830‚ 28669401‚ 29263834‚ 29391254‚ 32595695‚ 32628740 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 (rs750325275, gnomAD 0.04%). This variant has been observed in individuals with Roifman syndrome (PMID: 26522830, 28669401, 29263834, 29391254, 32595695). It has also been observed to segregate with disease in related individuals. This variant is also known as c.196-570C>T and 122288471 G>A. ClinVar contains an entry for this variant (Variation ID: 218082). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Functional studies have shown that this variant disrupts ncRNA function (PMID: 32628740). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Nov 02, 2015)	no assertion criteria provided Method: literature only	ROIFMAN SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000257313.2 First in ClinVar: Nov 22, 2015 Last updated: May 01, 2017	Publications: PubMed (1) PubMed: 26522830 Comment on evidence: For discussion of the 16G-A transition in the RNU4ATAC gene (GenBank NR_023343) that was found in compound heterozygous state in a Lebanese sister and brother … (more) For discussion of the 16G-A transition in the RNU4ATAC gene (GenBank NR_023343) that was found in compound heterozygous state in a Lebanese sister and brother with Roifman syndrome (RFMN; 616651) by Merico et al. (2015), see 601428.0001. (less)
Likely pathogenic (-)	no assertion criteria provided Method: research	Roifman syndrome Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV001161808.1 First in ClinVar: Feb 27, 2020 Last updated: Feb 27, 2020	Publications: PubMed (1) PubMed: 32581362 Observation 1: Number of individuals with the variant: 1 Sex: male Observation 2: Number of individuals with the variant: 1 Sex: female Observation 3: Number of individuals with the variant: 1 Sex: male
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Comment:

The NR_023343.1:n.16G>A a non coding transcript variant has been observed in the homozygous state or as a compound heterozygous, in trans with another disease-causing variant in association with autosomal recessive Roifman syndrome [MIM#616651] or autosomal recessivemicrocephalic osteodysplastic primordial dwarfism type 1 (MOPD1) [MIM#210710] [PMID: 29391254; PMID: 29263834; PMID:26522830]. The variant has 0.014% allele frequency in the gnomAD database (23 out of 161,196 heterozygous alleles) indicating this is a rare variant. Based on the available evidence, the variant n.16G>A is classified as Pathogenic

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 (rs750325275, gnomAD 0.04%). This variant has been observed in individuals with Roifman syndrome (PMID: 26522830, 28669401, 29263834, 29391254, 32595695). It has also been observed to segregate with disease in related individuals. This variant is also known as c.196-570C>T and 122288471 G>A. ClinVar contains an entry for this variant (Variation ID: 218082). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Functional studies have shown that this variant disrupts ncRNA function (PMID: 32628740). For these reasons, this variant has been 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
Clinical interpretation of variants identified in RNU4ATAC, a non-coding spliceosomal gene.	Benoit-Pilven C	PloS one	2020	PMID: 32628740
Parallel Tests of Whole Exome Sequencing and Copy Number Variant Sequencing Increase the Diagnosis Yields of Rare Pediatric Disorders.	Hu X	Frontiers in genetics	2020	PMID: 32595695
Whole-genome sequencing of patients with rare diseases in a national health system.	Turro E	Nature	2020	PMID: 32581362
Abnormal differentiation of B cells and megakaryocytes in patients with Roifman syndrome.	Heremans J	The Journal of allergy and clinical immunology	2018	PMID: 29391254
A homozygous mutation in the stem II domain of RNU4ATAC causes typical Roifman syndrome.	Dinur Schejter Y	NPJ genomic medicine	2017	PMID: 29263834
A Fast Association Test for Identifying Pathogenic Variants Involved in Rare Diseases.	Greene D	American journal of human genetics	2017	PMID: 28669401
Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing.	Merico D	Nature communications	2015	PMID: 26522830

Text-mined citations for rs750325275 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_001395891.1(CLASP1):c.196-570C>T

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs750325275 ...