VCV000100583.56 - ClinVar

NM_012210.4(TRIM32):c.1222C>T (p.Arg408Cys)

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.

(14)

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
Uncertain significance(4); Likely benign(7)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_012210.4(TRIM32):c.1222C>T (p.Arg408Cys)

Variation ID: 100583 Accession: VCV000100583.56

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q33.1 9: 116698964 (GRCh38) [ NCBI UCSC ] 9: 119461243 (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 25, 2014	Oct 20, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001365068.1:c.2806+26807G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_012210.4:c.1222C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_036342.2:p.Arg408Cys	missense
NM_001099679.2:c.1222C>T	NP_001093149.1:p.Arg408Cys	missense
NM_001365069.1:c.2794+26807G>A		intron variant
NM_001379048.1:c.1222C>T	NP_001365977.1:p.Arg408Cys	missense
NM_001379049.1:c.1222C>T	NP_001365978.1:p.Arg408Cys	missense
NM_001379050.1:c.1222C>T	NP_001365979.1:p.Arg408Cys	missense
NM_014010.5:c.2653+26807G>A		intron variant
NC_000009.12:g.116698964C>T
NC_000009.11:g.119461243C>T
NG_011619.1:g.16663C>T
NG_021409.2:g.721094G>A
LRG_211:g.16663C>T
LRG_211t1:c.1222C>T	LRG_211p1:p.Arg408Cys
	Q13049:p.Arg408Cys

... more HGVS ... less HGVS

Protein change

R408C

Other names

Canonical SPDI

NC_000009.12:116698963: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.

0.00080 (T)

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

1000 Genomes Project 0.00080

1000 Genomes Project 30x 0.00109

The Genome Aggregation Database (gnomAD) 0.00113

Trans-Omics for Precision Medicine (TOPMed) 0.00135

Exome Aggregation Consortium (ExAC) 0.00143

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00146

The Genome Aggregation Database (gnomAD), exomes 0.00149

Links

ClinGen: CA228919 UniProtKB: Q13049#VAR_038809 dbSNP: rs3747835 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.
not provided	Conflicting interpretations of pathogenicity (7)	criteria provided, conflicting classifications	Aug 3, 2021	RCV000086966.39
not specified	Likely benign (3)	criteria provided, multiple submitters, no conflicts	Nov 7, 2022	RCV000244938.13
Bardet-Biedl syndrome 11	Likely benign (1)	criteria provided, single submitter	Dec 10, 2023	RCV000626297.7
Sarcotubular myopathy	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Aug 31, 2021	RCV001166672.6
Bardet-Biedl syndrome	Likely benign (1)	criteria provided, single submitter	Jan 31, 2024	RCV001084393.8

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 benign (Nov 19, 2019)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV001475698.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021	Publications: PubMed (1) PubMed: 22025579
Uncertain significance (May 21, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001714311.1 First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021	Number of individuals with the variant: 1
Likely benign (Nov 07, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002766362.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (3) PubMed: 22025579‚ 31624253‚ 29921608 Comment: Variant summary: TRIM32 c.1222C>T (p.Arg408Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging … (more) Variant summary: TRIM32 c.1222C>T (p.Arg408Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 250724 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is higher than the estimated maximal expected allele frequency for a pathogenic variant in TRIM32 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive phenotype (0.0013), suggesting that the variant is benign. The variant, c.1222C>T, has been reported in the literature in individuals affected with various phenotypes, however without strong evidence for causality (e.g. Song_2011, Johnson_2019, Watkins_2019). These reports do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant as likely pathogenic (n=1), VUS (n=3), likely benign (n=4). Based on the evidence outlined above, the variant was classified as likely benign. (less)
Likely benign (Aug 03, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000491228.3 First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023	Comment: Previously reported in one individual with Usher syndrome; however, no second variant in the TRIM32 gene, as would be expected with autosomal recessive inheritance, was … (more) Previously reported in one individual with Usher syndrome; however, no second variant in the TRIM32 gene, as would be expected with autosomal recessive inheritance, was detected in this individual (Song et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22025579, 19349376) (less)
Likely benign (Dec 10, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 11 Affected status: yes Allele origin: inherited	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000746958.4 First in ClinVar: Apr 29, 2018 Last updated: Dec 24, 2023	Sex: male Geographic origin: Iran
Likely benign (Jan 31, 2024)	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: SCV000552160.8 First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000311880.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Likely benign (Dec 10, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000227409.5 First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018	Publications: PubMed (1) PubMed: 22025579 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TRIM32 Number of individuals with the variant: 23 Sex: mixed
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Sarcotubular myopathy Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001329070.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (Aug 31, 2021)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Sarcotubular myopathy Affected status: unknown Allele origin: germline	New York Genome Center Accession: SCV002764358.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022	Clinical Features: Type 2 diabetes mellitus (present) Secondary finding: no
Uncertain significance (Mar 01, 2018)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001155716.27 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 2
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001921747.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001970459.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: not provided	NEI Ophthalmic Genomics Laboratory, National Institutes of Health Accession: SCV000119219.1 First in ClinVar: Feb 25, 2014 Last updated: Feb 25, 2014
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Comment:

Variant summary: TRIM32 c.1222C>T (p.Arg408Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 250724 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is higher than the estimated maximal expected allele frequency for a pathogenic variant in TRIM32 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive phenotype (0.0013), suggesting that the variant is benign. The variant, c.1222C>T, has been reported in the literature in individuals affected with various phenotypes, however without strong evidence for causality (e.g. Song_2011, Johnson_2019, Watkins_2019). These reports do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant as likely pathogenic (n=1), VUS (n=3), likely benign (n=4). Based on the evidence outlined above, the variant was classified as likely benign.

Comment:

Previously reported in one individual with Usher syndrome; however, no second variant in the TRIM32 gene, as would be expected with autosomal recessive inheritance, was detected in this individual (Song et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22025579, 19349376)

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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
De novo and recessive forms of congenital heart disease have distinct genetic and phenotypic landscapes.	Watkins WS	Nature communications	2019	PMID: 31624253
Extending the clinical and mutational spectrum of TRIM32-related myopathies in a non-Hutterite population.	Johnson K	Journal of neurology, neurosurgery, and psychiatry	2019	PMID: 29921608
High-throughput retina-array for screening 93 genes involved in inherited retinal dystrophy.	Song J	Investigative ophthalmology & visual science	2011	PMID: 22025579
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TRIM32	-	-	-	-

Text-mined citations for rs3747835 ...

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 20, 2024

ClinVar Genomic variation as it relates to human health

NM_012210.4(TRIM32):c.1222C>T (p.Arg408Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs3747835 ...