NM_005422.4(TECTA):c.2444C>T (p.Thr815Met) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Oct 23, 2023
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000662344.17

Allele description [Variation Report for NM_005422.4(TECTA):c.2444C>T (p.Thr815Met)]

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

Genes:

LOC126861365:P300/CBP strongly-dependent group 1 enhancer GRCh37_chr11:121000154-121001353 [Gene]
TBCEL-TECTA:TBCEL-TECTA readthrough [Gene - HGNC]
TECTA:tectorin alpha [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q23.3

Genomic location:

Preferred name:

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

HGVS:

NC_000011.10:g.121129714C>T
NG_011633.1:g.32049C>T
NG_085864.1:g.370C>T
NM_001378761.1:c.3401C>T
NM_005422.4:c.2444C>TMANE SELECT
NP_001365690.1:p.Thr1134Met
NP_005413.2:p.Thr815Met
NP_005413.2:p.Thr815Met
NC_000011.9:g.121000423C>T
NM_005422.2:c.2444C>T
O75443:p.Thr815Met

Protein change:

T1134M

Links:

UniProtKB: O75443#VAR_066082; dbSNP: rs111759871

NCBI 1000 Genomes Browser:

rs111759871

Molecular consequence:

NM_001378761.1:c.3401C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005422.4:c.2444C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000342652	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions)	Uncertain significance (Jul 11, 2018)	germline	clinical testing	Citation Link,
SCV000784711	GenomeConnect, ClinGen	no classification provided	not provided	unknown	phenotyping only
SCV001553612	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Uncertain significance	unknown	clinical testing
SCV001781834	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Aug 24, 2021)	germline	clinical testing	Citation Link,
SCV002371837	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Oct 23, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	phenotyping only

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Eurofins Ntd Llc (ga), SCV000342652.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		2	not provided	not provided	not provided

From GenomeConnect, ClinGen, SCV000784711.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	phenotyping only	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	validation		not provided	not provided	not provided	not provided

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001553612.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV001781834.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002371837.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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