VCV000005290.32 - ClinVar

NM_003193.5(TBCE):c.155_166del (p.Ser52_Gly55del)

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.

(14)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003193.5(TBCE):c.155_166del (p.Ser52_Gly55del)

Variation ID: 5290 Accession: VCV000005290.32

Type and length

Deletion, 12 bp

Location

Cytogenetic: 1q42.3 1: 235401553-235401564 (GRCh38) [ NCBI UCSC ] 1: 235564868-235564879 (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	Jun 9, 2016	Sep 29, 2024	Aug 14, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_003193.5:c.155_166del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003184.1:p.Ser52_Gly55del	inframe deletion
NM_001079515.3:c.155_166del	NP_001072983.1:p.Ser52_Gly55del	inframe deletion
NM_001287801.2:c.155_166del	NP_001274730.1:p.Ser52_Gly55del	inframe deletion
NM_001287802.2:c.-210-12876_-210-12865del		intron variant
NM_003193.4:c.155_166delGCCACGAAGGGA
NC_000001.11:g.235401557_235401568del
NC_000001.10:g.235564872_235564883del
NG_009230.1:g.39145_39156del

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000001.11:235401552:GGGAGCCACGAAGGGA:GGGA

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

ClinGen: CA212825 OMIM: 604934.0001 dbSNP: rs767004810 VarSome

Comment on variant

NCBI staff reviewed the sequence information reported in PubMed 12389028 Fig. 2a to determine the location of this allele on the current reference sequence.

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.
TBCE		-	-	GRCh38 GRCh38 GRCh37	-	-

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.
Hypoparathyroidism-retardation-dysmorphism syndrome	Pathogenic/Likely pathogenic (8)	criteria provided, multiple submitters, no conflicts	May 22, 2022	RCV000005608.12
Autosomal recessive Kenny-Caffey syndrome	Pathogenic (1)	no assertion criteria provided	Nov 1, 2002	RCV000191990.7
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Aug 14, 2024	RCV000224858.15
Encephalopathy, progressive, with amyotrophy and optic atrophy	Pathogenic (1)	criteria provided, single submitter	Mar 25, 2024	RCV003989279.2

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.
Pathogenic (Dec 18, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000280889.1 First in ClinVar: Jun 09, 2016 Last updated: Jun 09, 2016
Pathogenic (Dec 30, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypoparathyroidism-retardation-dysmorphism syndrome Affected status: yes Allele origin: unknown	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University Accession: SCV000891681.1 First in ClinVar: Jan 06, 2017 Last updated: Jan 06, 2017	Publications: PubMed (1) PubMed: 25097779 Geographic origin: Middle East
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypoparathyroidism-retardation-dysmorphism syndrome Affected status: yes Allele origin: germline	Pathology and Clinical Laboratory Medicine, King Fahad Medical City Accession: SCV000996294.1 First in ClinVar: Oct 19, 2019 Last updated: Oct 19, 2019	Number of individuals with the variant: 10 Ethnicity/Population group: Arab Geographic origin: Middle East
Pathogenic (Jul 20, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypoparathyroidism-retardation-dysmorphism syndrome Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV002028329.1 First in ClinVar: Dec 04, 2021 Last updated: Dec 04, 2021
Pathogenic (Jan 13, 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: SCV003524137.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 12389028‚ 20152369‚ 26231322‚ 30080992 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 5290). This variant has been observed … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 5290). This variant has been observed in individuals with hypoparathyroidism-retardation-dysmorphism syndrome (PMID: 12389028, 20152369, 26231322, 30080992). It is commonly reported in individuals of Middle Eastern ancestry (PMID: 12389028, 30080992). This variant is present in population databases (rs767004810, gnomAD 0.006%). This variant, c.155_166del, results in the deletion of 4 amino acid(s) of the TBCE protein (p.Ser52_Gly55del), but otherwise preserves the integrity of the reading frame. (less)
Pathogenic (Mar 25, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Encephalopathy, progressive, with amyotrophy and optic atrophy Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004805967.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Pathogenic (Aug 14, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001820079.2 First in ClinVar: Sep 08, 2021 Last updated: Sep 29, 2024	Comment: In-frame deletion of 4 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with … (more) In-frame deletion of 4 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30080992, 29620724, 20152369, 26336027, 25097779, 30049826, 30638765, 26231322, 31589614, 36258138, 34374989, 35935360, 12389028) (less)
Likely pathogenic (Mar 16, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypoparathyroidism-retardation-dysmorphism syndrome Affected status: yes Allele origin: inherited	Centre for Translational Omics - GOSgene, University College London Accession: SCV000778576.1 First in ClinVar: Jan 06, 2017 Last updated: Jan 06, 2017
Pathogenic (May 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypoparathyroidism-retardation-dysmorphism syndrome Affected status: yes Allele origin: germline	3billion Accession: SCV002521836.1 First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022	Publications: PubMed (7) PubMed: 30638765‚ 26231322‚ 20152369‚ 25097779‚ 12389028‚ 30080992‚ 26336027 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Inframe deletion located in a nonrepeat region: … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Inframe deletion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:12389028). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:12389028, 20152369, 25097779, 26231322, 26336027, 30080992, 30638765). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Hypoparathyroidism (present) , Severe failure to thrive (present) , Hypocalcemic seizures (present) , Hypocalcemia (present)
Pathogenic (Jan 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002018933.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Feb 05, 2020)	no assertion criteria provided Method: clinical testing	Hypoparathyroidism-retardation-dysmorphism syndrome Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001190740.1 First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020
Pathogenic (Apr 01, 2023)	no assertion criteria provided Method: clinical testing	Hypoparathyroidism-retardation-dysmorphism syndrome Affected status: yes Allele origin: germline	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) Accession: SCV003927852.1 First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023
Pathogenic (Nov 01, 2002)	no assertion criteria provided Method: literature only	HYPOPARATHYROIDISM-RETARDATION-DYSMORPHISM SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000025790.4 First in ClinVar: Apr 04, 2013 Last updated: Jul 22, 2023	Publications: PubMed (2) PubMed: 12389028‚ 26336027 Comment on evidence: Parvari et al. (2002) demonstrated homozygosity for a 12-bp deletion in the second coding exon of the TBCE gene in all Middle Eastern individuals with … (more) Parvari et al. (2002) demonstrated homozygosity for a 12-bp deletion in the second coding exon of the TBCE gene in all Middle Eastern individuals with hypoparathyroidism-retardation-dysmorphism syndrome (HRDS; 241410) whom they evaluated (more than 50). The deletion was not present in more than 350 control chromosomes from Arab individuals. All the Middle Eastern subjects studied by Parvari et al. (2002) had the 12-bp deletion in the TBCE gene; however, the phenotype in 8 pedigrees with 13 affected individuals was that of autosomal recessive Kenny-Caffey syndrome (KCS1; 244460), differing from the phenotype in HRDS families (17 Saudi pedigrees, 27 affected individuals; 9 Israeli pedigrees, 25 affected individuals) owing to the additional presence of medullary stenosis of the long bones, calvarial osteosclerosis, and susceptibility to bacterial infection. The presence of patchy osteosclerosis in the long bones of some Saudi patients with HRDS and deaths secondary to sepsis in some Israeli Bedouin individuals with HRDS suggested variable expression of these phenotypic features in a pedigree-specific fashion. In a female infant, born of consanguineous Moroccan parents, with HRDS, Ratbi et al. (2015) identified homozygosity for the 12-bp deletion (c.155_166del12) that was previously found only in patients of Middle Eastern descent. The findings were consistent with the history of Arab migration to Morocco with the expansion of Islam to North Africa in the 7th century. (less)
Pathogenic (Nov 01, 2002)	no assertion criteria provided Method: literature only	KENNY-CAFFEY SYNDROME, TYPE 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000246253.3 First in ClinVar: Oct 01, 2015 Last updated: Jul 22, 2023	Publications: PubMed (2) PubMed: 12389028‚ 26336027 Comment on evidence: Parvari et al. (2002) demonstrated homozygosity for a 12-bp deletion in the second coding exon of the TBCE gene in all Middle Eastern individuals with … (more) Parvari et al. (2002) demonstrated homozygosity for a 12-bp deletion in the second coding exon of the TBCE gene in all Middle Eastern individuals with hypoparathyroidism-retardation-dysmorphism syndrome (HRDS; 241410) whom they evaluated (more than 50). The deletion was not present in more than 350 control chromosomes from Arab individuals. All the Middle Eastern subjects studied by Parvari et al. (2002) had the 12-bp deletion in the TBCE gene; however, the phenotype in 8 pedigrees with 13 affected individuals was that of autosomal recessive Kenny-Caffey syndrome (KCS1; 244460), differing from the phenotype in HRDS families (17 Saudi pedigrees, 27 affected individuals; 9 Israeli pedigrees, 25 affected individuals) owing to the additional presence of medullary stenosis of the long bones, calvarial osteosclerosis, and susceptibility to bacterial infection. The presence of patchy osteosclerosis in the long bones of some Saudi patients with HRDS and deaths secondary to sepsis in some Israeli Bedouin individuals with HRDS suggested variable expression of these phenotypic features in a pedigree-specific fashion. In a female infant, born of consanguineous Moroccan parents, with HRDS, Ratbi et al. (2015) identified homozygosity for the 12-bp deletion (c.155_166del12) that was previously found only in patients of Middle Eastern descent. The findings were consistent with the history of Arab migration to Morocco with the expansion of Islam to North Africa in the 7th century. (less)
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Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 5290). This variant has been observed in individuals with hypoparathyroidism-retardation-dysmorphism syndrome (PMID: 12389028, 20152369, 26231322, 30080992). It is commonly reported in individuals of Middle Eastern ancestry (PMID: 12389028, 30080992). This variant is present in population databases (rs767004810, gnomAD 0.006%). This variant, c.155_166del, results in the deletion of 4 amino acid(s) of the TBCE protein (p.Ser52_Gly55del), but otherwise preserves the integrity of the reading frame.

Comment:

In-frame deletion of 4 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30080992, 29620724, 20152369, 26336027, 25097779, 30049826, 30638765, 26231322, 31589614, 36258138, 34374989, 35935360, 12389028)

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Inframe deletion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:12389028). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:12389028, 20152369, 25097779, 26231322, 26336027, 30080992, 30638765). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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
Clinical features and tubulin folding cofactor E gene analysis in Iranian patients with Sanjad-Sakati syndrome.	Aminzadeh M	Jornal de pediatria	2020	PMID: 30080992
Additional Tunisian patients with Sanjad-Sakati syndrome: A review toward a consensus on diagnostic criteria.	Touati A	Archives de pediatrie : organe officiel de la Societe francaise de pediatrie	2019	PMID: 30638765
The Bedouin mutation c.155-166del of the TBCE gene in a patient with Sanjad-Sakati syndrome of Moroccan origin.	Ratbi I	Annals of Saudi medicine	2015	PMID: 26336027
Sanjad-Sakati syndrome in a Tunisian child.	Kerkeni E	Archives de pediatrie : organe officiel de la Societe francaise de pediatrie	2015	PMID: 26231322
New Ocular Associations in Sanjad-Sakati Syndrome: Case report from Oman.	Haider AS	Sultan Qaboos University medical journal	2014	PMID: 25097779
Visceral myopathy causing chronic intestinal pseudoobstruction and intestinal failure in a child with Sanjad-Sakati syndrome.	Pal K	Journal of pediatric surgery	2010	PMID: 20152369
Mutation of TBCE causes hypoparathyroidism-retardation-dysmorphism and autosomal recessive Kenny-Caffey syndrome.	Parvari R	Nature genetics	2002	PMID: 12389028

Text-mined citations for rs767004810 ...

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 Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_003193.5(TBCE):c.155_166del (p.Ser52_Gly55del)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs767004810 ...