NM_005993.5(TBCD):c.988C>T (p.Gln330Ter) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 9, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000578893.2

Allele description [Variation Report for NM_005993.5(TBCD):c.988C>T (p.Gln330Ter)]

NM_005993.5(TBCD):c.988C>T (p.Gln330Ter)

Gene:

TBCD:tubulin folding cofactor D [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q25.3

Genomic location:

Preferred name:

NM_005993.5(TBCD):c.988C>T (p.Gln330Ter)

HGVS:

NC_000017.11:g.82805912C>T
NG_011721.1:g.58849C>T
NM_005993.5:c.988C>TMANE SELECT
NP_005984.3:p.Gln330Ter
NC_000017.10:g.80763788C>T
NM_005993.4:c.988C>T

Protein change:

Q330*

Links:

dbSNP: rs1419604407

NCBI 1000 Genomes Browser:

rs1419604407

Molecular consequence:

NM_005993.5:c.988C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000681126	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Dec 6, 2018)	germline	clinical testing	Citation Link,
SCV004272509	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 9, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27666370, 27666374, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000681126

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Dec 6, 2018)

germline

clinical testing

Citation Link,

SCV004272509

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 9, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Biallelic Mutations in TBCD, Encoding the Tubulin Folding Cofactor D, Perturb Microtubule Dynamics and Cause Early-Onset Encephalopathy.

Flex E, Niceta M, Cecchetti S, Thiffault I, Au MG, Capuano A, Piermarini E, Ivanova AA, Francis JW, Chillemi G, Chandramouli B, Carpentieri G, Haaxma CA, Ciolfi A, Pizzi S, Douglas GV, Levine K, Sferra A, Dentici ML, Pfundt RR, Le Pichon JB, Farrow E, et al.

Am J Hum Genet. 2016 Oct 6;99(4):962-973. doi: 10.1016/j.ajhg.2016.08.003. Epub 2016 Sep 22.

PubMed [citation]

PMID:: 27666370
PMCID:: PMC5065658

Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy.

Miyake N, Fukai R, Ohba C, Chihara T, Miura M, Shimizu H, Kakita A, Imagawa E, Shiina M, Ogata K, Okuno-Yuguchi J, Fueki N, Ogiso Y, Suzumura H, Watabe Y, Imataka G, Leong HY, Fattal-Valevski A, Kramer U, Miyatake S, Kato M, Okamoto N, et al.

Am J Hum Genet. 2016 Oct 6;99(4):950-961. doi: 10.1016/j.ajhg.2016.08.005. Epub 2016 Sep 22.

PubMed [citation]

PMID:: 27666374
PMCID:: PMC5065661

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000681126.1

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

Description

The Q330X variant in the TBCD gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q330X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret Q330X as a pathogenic variant.

#	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 Invitae, SCV004272509.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Gln330*) in the TBCD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TBCD are known to be pathogenic (PMID: 27666370, 27666374). This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with TBCD-related conditions. ClinVar contains an entry for this variant (Variation ID: 489140). For these reasons, this variant has been classified as Pathogenic.

#	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: May 1, 2024

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