VCV002659455.13 - ClinVar

NM_002160.4(TNC):c.3637G>A (p.Val1213Ile)

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.

Conflicting classifications of pathogenicity
Uncertain significance(1); Likely benign(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002160.4(TNC):c.3637G>A (p.Val1213Ile)

Variation ID: 2659455 Accession: VCV002659455.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q33.1 9: 115063919 (GRCh38) [ NCBI UCSC ] 9: 117826198 (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	Nov 20, 2023	Oct 20, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002160.4:c.3637G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002151.2:p.Val1213Ile	missense
NM_001410991.1:c.3637G>A	NP_001397920.1:p.Val1213Ile	missense
NM_002160.3:c.3637G>A
NC_000009.12:g.115063919C>T
NC_000009.11:g.117826198C>T
NG_029637.1:g.59339G>A
NG_085241.1:g.857C>T

... more HGVS ... less HGVS

Protein change

V1213I

Other names

Canonical SPDI

NC_000009.12:115063918: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.

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.
LOC126860741	-	-	-	GRCh38	-	26
TNC		-	-	GRCh38 GRCh37	421	478

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	Likely benign (1)	criteria provided, single submitter	Oct 1, 2023	RCV003430220.10
TNC-related disorder	Likely benign (1)	no assertion criteria provided	Jan 10, 2023	RCV003966435.2
not specified	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Jan 31, 2024	RCV003988115.2

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 benign (Jan 31, 2024)	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: SCV004804056.1 First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024	Publications: PubMed (1) PubMed: 36597107 Comment: Variant summary: TNC c.3637G>A (p.Val1213Ile) results in a conservative amino acid change located in the fibronectin type III domain (IPR003961) of the encoded protein sequence. … (more) Variant summary: TNC c.3637G>A (p.Val1213Ile) results in a conservative amino acid change located in the fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 1614020 control chromosomes (i.e. 77 individuals) in the gnomAD database. This suggests the variant is not likely to be associated with a highly penetrant autosomal dominant disorder. c.3637G>A has been reported in the literature as a VUS in a setting of multigene panel testing in an individual affected with Deafness, however, it was also found in multiple ethnically-matched healthy controls (Ma_2023). This report does not provide unequivocal conclusions about association of the variant with Autosomal Dominant Deafness, 56. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 36597107). ClinVar contains an entry for this variant (Variation ID: 2659455). Based on the evidence outlined above, the variant was classified as likely benign. (less)
Uncertain significance (Sep 23, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV004969650.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Comment: The c.3637G>A (p.V1213I) alteration is located in exon 12 (coding exon 11) of the TNC gene. This alteration results from a G to A substitution … (more) The c.3637G>A (p.V1213I) alteration is located in exon 12 (coding exon 11) of the TNC gene. This alteration results from a G to A substitution at nucleotide position 3637, causing the valine (V) at amino acid position 1213 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Likely benign (Oct 01, 2023)	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: SCV004160635.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: TNC: BP4, BS2 Number of individuals with the variant: 1
Likely benign (Jan 10, 2023)	no assertion criteria provided Method: clinical testing	TNC-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004781580.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: 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).

Comment:

Variant summary: TNC c.3637G>A (p.Val1213Ile) results in a conservative amino acid change located in the fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 1614020 control chromosomes (i.e. 77 individuals) in the gnomAD database. This suggests the variant is not likely to be associated with a highly penetrant autosomal dominant disorder. c.3637G>A has been reported in the literature as a VUS in a setting of multigene panel testing in an individual affected with Deafness, however, it was also found in multiple ethnically-matched healthy controls (Ma_2023). This report does not provide unequivocal conclusions about association of the variant with Autosomal Dominant Deafness, 56. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 36597107). ClinVar contains an entry for this variant (Variation ID: 2659455). Based on the evidence outlined above, the variant was classified as likely benign.

Comment:

The c.3637G>A (p.V1213I) alteration is located in exon 12 (coding exon 11) of the TNC gene. This alteration results from a G to A substitution at nucleotide position 3637, causing the valine (V) at amino acid position 1213 to be replaced by an isoleucine (I). 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
Genetic screening of a Chinese cohort of children with hearing loss using a next-generation sequencing panel.	Ma J	Human genomics	2023	PMID: 36597107

Text-mined citations for this variant ...

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_002160.4(TNC):c.3637G>A (p.Val1213Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...