VCV000039680.5 - ClinVar

NM_015214.3(DDHD2):c.1546C>T (p.Arg516Ter)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_015214.3(DDHD2):c.1546C>T (p.Arg516Ter)

Variation ID: 39680 Accession: VCV000039680.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8p11.23 8: 38252216 (GRCh38) [ NCBI UCSC ] 8: 38109734 (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	Sep 17, 2015	Feb 28, 2024	Feb 23, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_015214.3:c.1546C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_056029.2:p.Arg516Ter	nonsense
NM_001164232.2:c.1546C>T	NP_001157704.1:p.Arg516Ter	nonsense
NM_001362911.2:c.1546C>T	NP_001349840.1:p.Arg516Ter	nonsense
NM_001362912.2:c.1546C>T	NP_001349841.1:p.Arg516Ter	nonsense
NM_001362913.2:c.1456C>T	NP_001349842.1:p.Arg486Ter	nonsense
NM_001362914.2:c.1546C>T	NP_001349843.1:p.Arg516Ter	nonsense
NR_156416.2:n.1761C>T		non-coding transcript variant
NR_156417.2:n.1761C>T		non-coding transcript variant
NC_000008.11:g.38252216C>T
NC_000008.10:g.38109734C>T
NG_033875.1:g.25726C>T

... more HGVS ... less HGVS

Protein change

R516*, R486*

Other names

Canonical SPDI

NC_000008.11:38252215: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.

The Genome Aggregation Database (gnomAD), exomes 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD) 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA130451 OMIM: 615003.0005 dbSNP: rs373856119 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.
DDHD2		-	-	GRCh38 GRCh37	305	387

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.
Hereditary spastic paraplegia 54	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Feb 23, 2023	RCV000032884.11

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 (Feb 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 54 Affected status: yes Allele origin: unknown	3billion Accession: SCV003842131.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Publications: PubMed (1) PubMed: 23176823 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). This variant was predicted to result in … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. It has been reported at least twice as pathogenic without evidence for the classification (PMID: 23176823). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Frequent falls (present) , Pectus excavatum (present) , Heart murmur (present) , Spastic paraparesis (present)
Pathogenic (Apr 17, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary spastic paraplegia 54 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002971179.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 23176823‚ 23486545 Comment: This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 23176823). It has also been observed to segregate with disease … (more) This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 23176823). It has also been observed to segregate with disease in related individuals. This sequence change creates a premature translational stop signal (p.Arg516*) in the DDHD2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DDHD2 are known to be pathogenic (PMID: 23176823, 23486545). This variant is present in population databases (rs373856119, gnomAD 0.01%). ClinVar contains an entry for this variant (Variation ID: 39680). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Dec 07, 2012)	no assertion criteria provided Method: literature only	SPASTIC PARAPLEGIA 54, AUTOSOMAL RECESSIVE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000056654.5 First in ClinVar: Apr 04, 2013 Last updated: Sep 17, 2015	Publications: PubMed (2) PubMed: 23176823‚ 16636240 Comment on evidence: In affected members of a large consanguineous Omani family with autosomal recessive spastic paraplegia-54 (SPG54; 615033), Schuurs-Hoeijmakers et al. (2012) identified a homozygous 1546C-T transition … (more) In affected members of a large consanguineous Omani family with autosomal recessive spastic paraplegia-54 (SPG54; 615033), Schuurs-Hoeijmakers et al. (2012) identified a homozygous 1546C-T transition in the DDHD2 gene, resulting in an arg516-to-ter (R516X) substitution. RT-PCR analysis suggested that the mutation resulted in nonsense-mediated mRNA decay. This family had previously been reported by Al-Yahyaee et al. (2006) as family A, showing linkage to chromosome 8p. (less)
Pathogenic (Dec 30, 2017)	no assertion criteria provided Method: curation	Hereditary spastic paraplegia 54 Affected status: yes Allele origin: unknown	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University Accession: SCV000891594.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Publications: PubMed (1) PubMed: 23176823 Geographic origin: Middle East

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. It has been reported at least twice as pathogenic without evidence for the classification (PMID: 23176823). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 23176823). It has also been observed to segregate with disease in related individuals. This sequence change creates a premature translational stop signal (p.Arg516*) in the DDHD2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DDHD2 are known to be pathogenic (PMID: 23176823, 23486545). This variant is present in population databases (rs373856119, gnomAD 0.01%). ClinVar contains an entry for this variant (Variation ID: 39680). 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
Mutations in phospholipase DDHD2 cause autosomal recessive hereditary spastic paraplegia (SPG54).	Gonzalez M	European journal of human genetics : EJHG	2013	PMID: 23486545
Mutations in DDHD2, encoding an intracellular phospholipase A(1), cause a recessive form of complex hereditary spastic paraplegia.	Schuurs-Hoeijmakers JH	American journal of human genetics	2012	PMID: 23176823
A novel locus for hereditary spastic paraplegia with thin corpus callosum and epilepsy.	Al-Yahyaee S	Neurology	2006	PMID: 16636240

Text-mined citations for rs373856119 ...

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_015214.3(DDHD2):c.1546C>T (p.Arg516Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs373856119 ...