VCV000372235.8 - ClinVar

NM_014026.6(DCPS):c.947C>T (p.Thr316Met)

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.

(5)

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.

Conflicting classifications of pathogenicity
Pathogenic(1); Uncertain significance(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_014026.6(DCPS):c.947C>T (p.Thr316Met)

Variation ID: 372235 Accession: VCV000372235.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q24.2 11: 126345546 (GRCh38) [ NCBI UCSC ] 11: 126215441 (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	Jan 7, 2017	Nov 24, 2024	Apr 4, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_014026.6:c.947C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_054745.1:p.Thr316Met	missense
NM_001350236.2:c.968C>T	NP_001337165.1:p.Thr323Met	missense
NC_000011.10:g.126345546C>T
NC_000011.9:g.126215441C>T
NG_053153.1:g.47246C>T

... more HGVS ... less HGVS

Protein change

T316M, T323M

Other names

DCPS, THR316MET (rs137941190)

Canonical SPDI

NC_000011.10:126345545: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.

0.00200 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00006

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

The Genome Aggregation Database (gnomAD), exomes 0.00120

1000 Genomes Project 30x 0.00172

1000 Genomes Project 0.00200

Trans-Omics for Precision Medicine (TOPMed) 0.00004

Links

ClinGen: CA6355201 OMIM: 610534.0003 dbSNP: rs137941190 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.
DCPS		-	-	GRCh38 GRCh37	32	154
GSEC	-	-	-	GRCh38	-	65

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.
Al-Raqad syndrome	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	Apr 4, 2024	RCV000412619.10

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 (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Al-Raqad syndrome Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002519480.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Uncertain significance (Apr 04, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Al-Raqad syndrome Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004810118.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024
Uncertain significance (Jun 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Al-Raqad syndrome (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004176646.3 First in ClinVar: Dec 17, 2023 Last updated: Nov 24, 2024	Comment: The observed missense c.947C>T(p.Thr316Met) variant in DCPS gene has been reported previously in compound heterozygous state in individuals affected with Al-Raqad syndrome (Ahmed I, et … (more) The observed missense c.947C>T(p.Thr316Met) variant in DCPS gene has been reported previously in compound heterozygous state in individuals affected with Al-Raqad syndrome (Ahmed I, et al., 2015; Zhou M, et al., 2015; Weil D, et al., 2020). This variant has also been observed to segregate with disease. In vitro decapping assays showed an ablation of decapping function for this variant (Ahmed I, et al., 2015). The p.Thr316Met variant has been reported with allele frequency of 0.1% in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic. Multiple lines of computational evidences (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid change at this position on DCPS gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Thr at position 316 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. However, additional functional studies will be required to prove the pathogenicity of this variant conclusively. For these reasons, this variant has been classified as Likely Pathogenic. (less) Clinical Features: Abnormality of the nervous system (present)
Pathogenic (Jul 29, 2019)	no assertion criteria provided Method: literature only	AL-RAQAD SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000490310.1 First in ClinVar: Jan 07, 2017 Last updated: Jan 07, 2017	Publications: PubMed (1) PubMed: 25701870 Comment on evidence: For discussion of the c.974C-T transition (rs137941190) in the DCPS gene, resulting in a thr316-to-met (T316M) substitution, that was found in compound heterozygous state in … (more) For discussion of the c.974C-T transition (rs137941190) in the DCPS gene, resulting in a thr316-to-met (T316M) substitution, that was found in compound heterozygous state in a patient with Al-Raqad syndrome (ARS; 616459) by Ahmed et al. (2015), see 610534.0002. (less)
Likely pathogenic (Jan 06, 2020)	no assertion criteria provided Method: curation	AL-RAQAD SYNDROME Affected status: unknown Allele origin: germline	Reproductive Health Research and Development, BGI Genomics Accession: SCV001142428.1 First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020	Comment: NM_014026.3:c.947C>T in the DCPS gene has an allele frequency of 0.01 in South Asian subpopulation in the gnomAD database. The p.Thr316Met (NM_014026.3:c.947C>T) variant has been … (more) NM_014026.3:c.947C>T in the DCPS gene has an allele frequency of 0.01 in South Asian subpopulation in the gnomAD database. The p.Thr316Met (NM_014026.3:c.947C>T) variant has been observed in three affected individuals from a large family, in trans with a splice site variant (c.636+1G>A) and were reported to segregate with intellectual disability. In vitro decapping assays showed an ablation of decapping function for both variants in DCPS (PMID: 25701870). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS3; PM3; PP1. (less)

Comment:

The observed missense c.947C>T(p.Thr316Met) variant in DCPS gene has been reported previously in compound heterozygous state in individuals affected with Al-Raqad syndrome (Ahmed I, et al., 2015; Zhou M, et al., 2015; Weil D, et al., 2020). This variant has also been observed to segregate with disease. In vitro decapping assays showed an ablation of decapping function for this variant (Ahmed I, et al., 2015). The p.Thr316Met variant has been reported with allele frequency of 0.1% in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic. Multiple lines of computational evidences (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid change at this position on DCPS gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Thr at position 316 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. However, additional functional studies will be required to prove the pathogenicity of this variant conclusively. For these reasons, this variant has been classified as Likely Pathogenic.

Comment:

NM_014026.3:c.947C>T in the DCPS gene has an allele frequency of 0.01 in South Asian subpopulation in the gnomAD database. The p.Thr316Met (NM_014026.3:c.947C>T) variant has been observed in three affected individuals from a large family, in trans with a splice site variant (c.636+1G>A) and were reported to segregate with intellectual disability. In vitro decapping assays showed an ablation of decapping function for both variants in DCPS (PMID: 25701870). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS3; PM3; PP1.

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
Mutations in DCPS and EDC3 in autosomal recessive intellectual disability indicate a crucial role for mRNA decapping in neurodevelopment.	Ahmed I	Human molecular genetics	2015	PMID: 25701870

Text-mined citations for rs137941190 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_014026.6(DCPS):c.947C>T (p.Thr316Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs137941190 ...