VCV000239724.11 - ClinVar

NM_004260.4(RECQL4):c.2412_2420del (p.Ala805_Arg807del)

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.

(4)

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_004260.4(RECQL4):c.2412_2420del (p.Ala805_Arg807del)

Variation ID: 239724 Accession: VCV000239724.11

Type and length

Deletion, 9 bp

Location

Cytogenetic: 8q24.3 8: 144513261-144513269 (GRCh38) [ NCBI UCSC ] 8: 145738644-145738652 (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 10, 2018	Feb 14, 2024	Jan 19, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004260.4:c.2412_2420del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004251.4:p.Ala805_Arg807del	inframe deletion
NM_004260.3:c.2412_2420delGGCCGGGCG		inframe deletion
NC_000008.11:g.144513263_144513271del
NC_000008.10:g.145738646_145738654del
NG_016430.2:g.9558_9566del
NG_033083.1:g.298_306del
LRG_277:g.9558_9566del
LRG_277t1:c.2412_2420del	LRG_277p1:p.Ala805_Arg807del

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000008.11:144513260:CGCCCGGCCCG:CG

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: CA4948299 dbSNP: rs766312203 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.
RECQL4		-	-	GRCh38 GRCh37	4469	4838

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.
Baller-Gerold syndrome	Pathogenic (1)	criteria provided, single submitter	Jan 19, 2024	RCV000234695.11
not provided	Likely pathogenic (1)	criteria provided, single submitter	Sep 22, 2021	RCV001731539.2
Rothmund-Thomson syndrome type 2	Likely pathogenic (1)	criteria provided, single submitter	Oct 26, 2021	RCV002243905.2
Baller-Gerold syndrome Rapadilino syndrome Rothmund-Thomson syndrome type 2	Likely pathogenic (1)	criteria provided, single submitter	Apr 26, 2022	RCV002500783.1

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 (Jan 19, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Baller-Gerold syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000288218.10 First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 28492532‚ 29642415‚ 31604778 Comment: This variant, c.2412_2420del, results in the deletion of 3 amino acid(s) of the RECQL4 protein (p.Ala805_Arg807del), but otherwise preserves the integrity of the reading frame. … (more) This variant, c.2412_2420del, results in the deletion of 3 amino acid(s) of the RECQL4 protein (p.Ala805_Arg807del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs766312203, gnomAD 0.06%). This variant has been observed in individual(s) with Rothmund-Thomson syndrome (PMID: 29642415, 31604778; Invitae). 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: 239724). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Oct 26, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Rothmund-Thomson syndrome type 2 Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002512442.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022	Comment: ACMG classification criteria: PS4 supporting, PM2 moderate, PM3 moderate, PM4 moderate Geographic origin: Brazil
Likely pathogenic (Apr 26, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Baller-Gerold syndrome Rapadilino syndrome Rothmund-Thomson syndrome type 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002813956.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Likely pathogenic (Sep 22, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001982112.2 First in ClinVar: Oct 30, 2021 Last updated: Mar 04, 2023	Comment: Identified in unrelated patients with RECQL4-related phenotype referred for genetic testing at GeneDx and in published literature (Colombo et al., 2018); In-frame deletion of 3 … (more) Identified in unrelated patients with RECQL4-related phenotype referred for genetic testing at GeneDx and in published literature (Colombo et al., 2018); In-frame deletion of 3 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29642415, 31604778) (less)

Comment:

This variant, c.2412_2420del, results in the deletion of 3 amino acid(s) of the RECQL4 protein (p.Ala805_Arg807del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs766312203, gnomAD 0.06%). This variant has been observed in individual(s) with Rothmund-Thomson syndrome (PMID: 29642415, 31604778; Invitae). 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: 239724). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.

Comment:

Identified in unrelated patients with RECQL4-related phenotype referred for genetic testing at GeneDx and in published literature (Colombo et al., 2018); In-frame deletion of 3 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29642415, 31604778)

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
Enrichment of heterozygous germline RECQL4 loss-of-function variants in pediatric osteosarcoma.	Maciaszek JL	Cold Spring Harbor molecular case studies	2019	PMID: 31604778
Rothmund-Thomson Syndrome: Insights from New Patients on the Genetic Variability Underpinning Clinical Presentation and Cancer Outcome.	Colombo EA	International journal of molecular sciences	2018	PMID: 29642415

Text-mined citations for rs766312203 ...

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_004260.4(RECQL4):c.2412_2420del (p.Ala805_Arg807del)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs766312203 ...