VCV002748819.3 - ClinVar

NM_007217.4(PDCD10):c.131T>G (p.Leu44Arg)

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.

(2)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_007217.4(PDCD10):c.131T>G (p.Leu44Arg)

Variation ID: 2748819 Accession: VCV002748819.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3q26.1 3: 167704861 (GRCh38) [ NCBI UCSC ] 3: 167422649 (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	Feb 14, 2024	Aug 11, 2024	Apr 24, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_007217.4:c.131T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_009148.2:p.Leu44Arg	missense
NM_145859.2:c.131T>G	NP_665858.1:p.Leu44Arg	missense
NM_145860.1:c.131T>G
NM_145860.2:c.131T>G	NP_665859.1:p.Leu44Arg	missense
NC_000003.12:g.167704861A>C
NC_000003.11:g.167422649A>C
NG_008158.1:g.35003T>G
LRG_651:g.35003T>G
LRG_651t1:c.131T>G	LRG_651p1:p.Leu44Arg

... more HGVS ... less HGVS

Protein change

L44R

Other names

Canonical SPDI

NC_000003.12:167704860:A:C

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

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.
PDCD10		-	-	GRCh38 GRCh37	174	211

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.
Cerebral cavernous malformation 3	Uncertain significance (1)	criteria provided, single submitter	Jul 31, 2023	RCV003497811.2
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Apr 24, 2024	RCV004369372.2

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.
Uncertain significance (Jul 31, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cerebral cavernous malformation 3 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004310953.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Comment: In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant … (more) In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with PDCD10-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 44 of the PDCD10 protein (p.Leu44Arg). (less)
Uncertain significance (Apr 24, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005003291.2 First in ClinVar: May 01, 2024 Last updated: Aug 11, 2024	Publications: PubMed (1) PubMed: 25122144 Comment: The c.131T>G (p.L44R) alteration is located in exon 3 (coding exon 2) of the PDCD10 gene. This alteration results from a T to G substitution … (more) The c.131T>G (p.L44R) alteration is located in exon 3 (coding exon 2) of the PDCD10 gene. This alteration results from a T to G substitution at nucleotide position 131, causing the leucine (L) at amino acid position 44 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Another alteration at the same codon, c.131T>C (p.L44P), has been detected in an individual with cerebral cavernous malformations (Shenkar, 2015). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)

Comment:

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with PDCD10-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 44 of the PDCD10 protein (p.Leu44Arg).

Comment:

The c.131T>G (p.L44R) alteration is located in exon 3 (coding exon 2) of the PDCD10 gene. This alteration results from a T to G substitution at nucleotide position 131, causing the leucine (L) at amino acid position 44 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Another alteration at the same codon, c.131T>C (p.L44P), has been detected in an individual with cerebral cavernous malformations (Shenkar, 2015). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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
Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations.	Shenkar R	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25122144

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_007217.4(PDCD10):c.131T>G (p.Leu44Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...