VCV000540484.42 - ClinVar

NM_015631.6(TCTN3):c.946A>G (p.Thr316Ala)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance(3); Likely benign(2)

5 out of 9 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_015631.6(TCTN3):c.946A>G (p.Thr316Ala)

Variation ID: 540484 Accession: VCV000540484.42

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q24.1 10: 95685579 (GRCh38) [ NCBI UCSC ] 10: 97445336 (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	May 28, 2018	Feb 23, 2026	Feb 4, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_015631.6:c.946A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_056446.4:p.Thr316Ala	missense
NM_001143973.2:c.651+916A>G		intron variant
NC_000010.11:g.95685579T>C
NC_000010.10:g.97445336T>C
NG_032953.1:g.13565A>G

... more HGVS ... less HGVS

Protein change

T316A

Other names

Canonical SPDI

NC_000010.11:95685578:T:C

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.

0.00020 (C)

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

The Genome Aggregation Database (gnomAD), exomes 0.00082

Trans-Omics for Precision Medicine (TOPMed) 0.00089

The Genome Aggregation Database (gnomAD) 0.00118

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

The Genome Aggregation Database (gnomAD) 0.00115

The Genome Aggregation Database (gnomAD), exomes 0.00115

Exome Aggregation Consortium (ExAC) 0.00125

Links

ClinGen: CA5621010 dbSNP: rs200042949 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.
TCTN3		-	-	GRCh38 GRCh37	523	642

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.
Joubert syndrome 18 Orofacial-digital syndrome IV	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	Feb 4, 2026	RCV000650532.20
not provided	Conflicting classifications of pathogenicity (5)	criteria provided, conflicting classifications	Jun 1, 2025	RCV001572868.36
not specified	Uncertain significance (1)	no assertion criteria provided	Jun 13, 2022	RCV003151118.9
TCTN3-related disorder	Likely benign (1)	no assertion criteria provided	Nov 7, 2022	RCV004533402.2

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.	Expand all rows Collapse all rows 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 (Jun 01, 2021) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV001825610.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Comment: show In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26582918) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Uncertain significance (Nov 03, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002011626.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: not provided Observation 1 Collection method: clinical testing Allele origin: germline Affected status: not provided

Uncertain significance (Jul 13, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Orofacial-digital syndrome IV Joubert syndrome 18 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Department of Pathology and Laboratory Medicine, Sinai Health System Accession: SCV006054795.1 First in ClinVar: Apr 28, 2025 Last updated: Apr 28, 2025	Observation: 1 Collection method: research Allele origin: germline Affected status: unknown Observation 1 Collection method: research Allele origin: germline Affected status: unknown

Likely benign (Jun 01, 2025) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	not provided	CeGaT Center for Human Genetics Tuebingen Accession: SCV004127153.20 First in ClinVar: Nov 20, 2023 Last updated: Jan 11, 2026	Comment: show TCTN3: BP4 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 4

Likely benign (Feb 04, 2026) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Joubert syndrome 18 Orofacial-digital syndrome IV Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000772378.9 First in ClinVar: May 28, 2018 Last updated: Feb 23, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001797903.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	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: SCV001966899.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Uncertain significance (Jun 13, 2022) N Not contributing to aggregate classification	no assertion criteria provided	not specified	Genetic Services Laboratory, University of Chicago Accession: SCV003840107.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Comment: show DNA sequence analysis of the TCTN3 gene demonstrated a sequence change, c.946A>G, in exon 8 that results in an amino acid change, p.Thr316Ala. This sequence change has been described in the gnomAD database with a frequency of 0.20% in the non-Finnish European subpopulation (dbSNP rs200042949). The p.Thr316Ala change affects a moderately conserved amino acid residue located in a domain of the TCTN3 protein that is known to be functional. The p.Thr316Ala substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in individuals with TCTN3-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Thr316Ala change remains unknown at this time. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Likely benign (Nov 07, 2022) N Not contributing to aggregate classification	no assertion criteria provided	TCTN3-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV004751636.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: show This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26582918)

Comment:

DNA sequence analysis of the TCTN3 gene demonstrated a sequence change, c.946A>G, in exon 8 that results in an amino acid change, p.Thr316Ala. This sequence change has been described in the gnomAD database with a frequency of 0.20% in the non-Finnish European subpopulation (dbSNP rs200042949). The p.Thr316Ala change affects a moderately conserved amino acid residue located in a domain of the TCTN3 protein that is known to be functional. The p.Thr316Ala substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in individuals with TCTN3-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Thr316Ala change remains unknown at this time.

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs200042949 ...

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 Mar 01, 2026