VCV000288521.15 - ClinVar

NM_005422.4(TECTA):c.2444C>T (p.Thr815Met)

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.

(6)

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(3); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005422.4(TECTA):c.2444C>T (p.Thr815Met)

Variation ID: 288521 Accession: VCV000288521.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q23.3 11: 121129714 (GRCh38) [ NCBI UCSC ] 11: 121000423 (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	Jul 16, 2018	Feb 14, 2024	Oct 23, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_005422.4:c.2444C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005413.2:p.Thr815Met	missense
NM_001378761.1:c.3401C>T	NP_001365690.1:p.Thr1134Met	missense
NC_000011.10:g.121129714C>T
NC_000011.9:g.121000423C>T
NG_011633.1:g.32049C>T
NG_085864.1:g.370C>T
	O75443:p.Thr815Met

... more HGVS ... less HGVS

Protein change

T815M, T1134M

Other names

Canonical SPDI

NC_000011.10:121129713: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.

0.00060 (T)

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

1000 Genomes Project 30x 0.00094

Exome Aggregation Consortium (ExAC) 0.00024

Trans-Omics for Precision Medicine (TOPMed) 0.00058

1000 Genomes Project 0.00060

The Genome Aggregation Database (gnomAD) 0.00060

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00085

Links

ClinGen: CA6326995 UniProtKB: O75443#VAR_066082 dbSNP: rs111759871 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.
LOC126861365	-	-	-	GRCh38	-	118
TBCEL-TECTA	-	-	-	GRCh38	-	1110
TECTA		-	-	GRCh38 GRCh37	6	1123

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 (5)	criteria provided, conflicting classifications	Oct 23, 2023	RCV000662344.17
Autosomal dominant nonsyndromic hearing loss 12	Uncertain significance (1)	criteria provided, single submitter	Jul 16, 2018	RCV001336814.1

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 11, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000342652.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TECTA Number of individuals with the variant: 2 Sex: mixed
Uncertain significance (Jul 16, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal dominant nonsyndromic hearing loss 12 Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001530311.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Uncertain significance (Aug 24, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001781834.3 First in ClinVar: Aug 14, 2021 Last updated: Mar 04, 2023	Comment: Reported heterozygous in association with hearing loss (Hildebrand et al., 2011) but no detailed clinical information available and is separately reported as having questionable pathogenicity … (more) Reported heterozygous in association with hearing loss (Hildebrand et al., 2011) but no detailed clinical information available and is separately reported as having questionable pathogenicity (Behlouli et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21520338, 25262649, 30245029, 27368438) (less)
Likely benign (Oct 23, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002371837.3 First in ClinVar: Apr 08, 2022 Last updated: Feb 14, 2024
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001553612.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: The TECTA p.Thr815Met variant was identified in 1 of 890 proband chromosomes (frequency: 0.0011) from individuals or families with autosomal dominant non-syndromic hearing loss (Hildebrand_2011_PMID:21520338). … (more) The TECTA p.Thr815Met variant was identified in 1 of 890 proband chromosomes (frequency: 0.0011) from individuals or families with autosomal dominant non-syndromic hearing loss (Hildebrand_2011_PMID:21520338). The variant was identified in dbSNP (ID: rs111759871), LOVD 3.0 and ClinVar (classified as uncertain significance by EGL Genetic Diagnostics). The variant was identified in control databases in 71 of 282874 chromosomes (1 homozygous) at a frequency of 0.000251 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 62 of 24966 chromosomes (freq: 0.002483), Other in 2 of 7228 chromosomes (freq: 0.000277), Latino in 6 of 35440 chromosomes (freq: 0.000169) and South Asian in 1 of 30616 chromosomes (freq: 0.000033), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), or European (non-Finnish) populations. The p.Thr815 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
not provided (-)	no classification provided Method: phenotyping only	Not Provided Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV000784711.1 First in ClinVar: Jul 16, 2018 Last updated: Jul 16, 2018	Comment: GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more) GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Short stature (present) , Abnormality of the parathyroid physiology (present) , Sensorineural hearing loss (present) , Abnormality of the intestine (present) , Abnormality of urine … (more) Short stature (present) , Abnormality of the parathyroid physiology (present) , Sensorineural hearing loss (present) , Abnormality of the intestine (present) , Abnormality of urine homeostasis (present) , Abnormality of the ureter (present) , Abnormality of the female genitalia (present) , Abnormal renal morphology (present) (less) Indication for testing: Diagnostic Age: 0-9 years Sex: female Method: Sanger Sequencing Testing laboratory: Molecular Otolaryngology and Renal Research Laboratories,University of Iowa Hospital and Clinics Date variant was reported to submitter: 2018-01-11 Testing laboratory interpretation: Benign

Comment:

Reported heterozygous in association with hearing loss (Hildebrand et al., 2011) but no detailed clinical information available and is separately reported as having questionable pathogenicity (Behlouli et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21520338, 25262649, 30245029, 27368438)

Comment:

The TECTA p.Thr815Met variant was identified in 1 of 890 proband chromosomes (frequency: 0.0011) from individuals or families with autosomal dominant non-syndromic hearing loss (Hildebrand_2011_PMID:21520338). The variant was identified in dbSNP (ID: rs111759871), LOVD 3.0 and ClinVar (classified as uncertain significance by EGL Genetic Diagnostics). The variant was identified in control databases in 71 of 282874 chromosomes (1 homozygous) at a frequency of 0.000251 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 62 of 24966 chromosomes (freq: 0.002483), Other in 2 of 7228 chromosomes (freq: 0.000277), Latino in 6 of 35440 chromosomes (freq: 0.000169) and South Asian in 1 of 30616 chromosomes (freq: 0.000033), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), or European (non-Finnish) populations. The p.Thr815 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain 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
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TECTA	-	-	-	-

Text-mined citations for rs111759871 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_005422.4(TECTA):c.2444C>T (p.Thr815Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs111759871 ...