VCV000007351.12 - ClinVar

NM_012210.4(TRIM32):c.388C>T (p.Pro130Ser)

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_012210.4(TRIM32):c.388C>T (p.Pro130Ser)

Variation ID: 7351 Accession: VCV000007351.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q33.1 9: 116698130 (GRCh38) [ NCBI UCSC ] 9: 119460409 (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	Apr 7, 2016	Oct 8, 2024	Dec 12, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001365068.1:c.2806+27641G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_012210.4:c.388C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_036342.2:p.Pro130Ser	missense
NM_001099679.2:c.388C>T	NP_001093149.1:p.Pro130Ser	missense
NM_001365069.1:c.2794+27641G>A		intron variant
NM_001379048.1:c.388C>T	NP_001365977.1:p.Pro130Ser	missense
NM_001379049.1:c.388C>T	NP_001365978.1:p.Pro130Ser	missense
NM_001379050.1:c.388C>T	NP_001365979.1:p.Pro130Ser	missense
NM_014010.5:c.2653+27641G>A		intron variant
NC_000009.12:g.116698130C>T
NC_000009.11:g.119460409C>T
NG_011619.1:g.15829C>T
NG_021409.2:g.721928G>A
LRG_211:g.15829C>T
LRG_211t1:c.388C>T	LRG_211p1:p.Pro130Ser
	Q13049:p.Pro130Ser

... more HGVS ... less HGVS

Protein change

P130S

Other names

Canonical SPDI

NC_000009.12:116698129: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) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA254151 UniProtKB: Q13049#VAR_038807 OMIM: 602290.0002 dbSNP: rs111033571 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.
ASTN2		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	178	972
TRIM32		-	-	GRCh38 GRCh37	-	773

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.
Bardet-Biedl syndrome 11	Pathogenic (1)	no assertion criteria provided	Feb 1, 2008	RCV000007776.11
Bardet-Biedl syndrome	Pathogenic (1)	criteria provided, single submitter	Dec 12, 2023	RCV000199127.9
TRIM32-related disorder	Likely pathogenic (1)	no assertion criteria provided	Nov 22, 2023	RCV003904817.2
not provided	Likely pathogenic (1)	criteria provided, single submitter	Feb 21, 2023	RCV003488330.2

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.
Likely pathogenic (Feb 21, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV004238771.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Pathogenic (Dec 12, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Bardet-Biedl syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000253915.6 First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024	Publications: PubMed (1) PubMed: 16606853 Comment: This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 130 of the TRIM32 protein (p.Pro130Ser). … (more) This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 130 of the TRIM32 protein (p.Pro130Ser). This variant is present in population databases (rs111033571, gnomAD 0.002%). This missense change has been observed in individual(s) with Bardet‚ÄìBiedl syndrome (PMID: 16606853). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7351). 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 tolerated. Experimental studies have shown that this missense change affects TRIM32 function (PMID: 16606853). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 01, 2008)	no assertion criteria provided Method: literature only	BARDET-BIEDL SYNDROME 11 (1 family) Affected status: not provided Allele origin: germline	OMIM Accession: SCV000027977.9 First in ClinVar: Apr 04, 2013 Last updated: Mar 10, 2024	Publications: PubMed (2) PubMed: 16606853‚ 17994549 Comment on evidence: By homozygosity mapping using high-density SNP genotyping, Chiang et al. (2006) identified the TRIM32 gene as the site of mutations causing Bardet-Biedl syndrome (BBS11; 615988) … (more) By homozygosity mapping using high-density SNP genotyping, Chiang et al. (2006) identified the TRIM32 gene as the site of mutations causing Bardet-Biedl syndrome (BBS11; 615988) in a small consanguineous Israeli Bedouin family. The specific mutation was a change of codon 130 from CCT (pro) to TCT (ser). The substitution was present in homozygous state in the affected individuals. In vitro functional expression studies by Saccone et al. (2008) demonstrated that the P130S-mutant protein maintained self-interaction ability. (less)
Likely pathogenic (Nov 22, 2023)	no assertion criteria provided Method: clinical testing	TRIM32-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004718540.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The TRIM32 c.388C>T variant is predicted to result in the amino acid substitution p.Pro130Ser. In a consanguineous family, this variant was reported in the homozygous … (more) The TRIM32 c.388C>T variant is predicted to result in the amino acid substitution p.Pro130Ser. In a consanguineous family, this variant was reported in the homozygous state in multiple individuals with Bardet-Biedl syndrome (Chiang et al. 2006. PubMed ID: 16606853). Zebrafish studies suggest this variant may affect protein function (Chiang et al. 2006. PubMed ID: 16606853; Zaghloul et al. 2010. PubMed ID: 20498079). This variant is reported in 0.0028% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-119460409-C-T). This variant is interpreted as likely pathogenic. (less)

Comment:

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 130 of the TRIM32 protein (p.Pro130Ser). This variant is present in population databases (rs111033571, gnomAD 0.002%). This missense change has been observed in individual(s) with Bardet‚ÄìBiedl syndrome (PMID: 16606853). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7351). 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 tolerated. Experimental studies have shown that this missense change affects TRIM32 function (PMID: 16606853). For these reasons, this variant has been classified as Pathogenic.

Comment:

The TRIM32 c.388C>T variant is predicted to result in the amino acid substitution p.Pro130Ser. In a consanguineous family, this variant was reported in the homozygous state in multiple individuals with Bardet-Biedl syndrome (Chiang et al. 2006. PubMed ID: 16606853). Zebrafish studies suggest this variant may affect protein function (Chiang et al. 2006. PubMed ID: 16606853; Zaghloul et al. 2010. PubMed ID: 20498079). This variant is reported in 0.0028% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-119460409-C-T). This variant is interpreted as likely 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 that impair interaction properties of TRIM32 associated with limb-girdle muscular dystrophy 2H.	Saccone V	Human mutation	2008	PMID: 17994549
Homozygosity mapping with SNP arrays identifies TRIM32, an E3 ubiquitin ligase, as a Bardet-Biedl syndrome gene (BBS11).	Chiang AP	Proceedings of the National Academy of Sciences of the United States of America	2006	PMID: 16606853

Text-mined citations for rs111033571 ...

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 13, 2024

ClinVar Genomic variation as it relates to human health

NM_012210.4(TRIM32):c.388C>T (p.Pro130Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs111033571 ...