NM_002968.3(SALL1):c.2050C>T (p.Gln684Ter) AND Townes-Brocks syndrome 1

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Oct 8, 2024
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:: RCV001029950.5

Allele description [Variation Report for NM_002968.3(SALL1):c.2050C>T (p.Gln684Ter)]

NM_002968.3(SALL1):c.2050C>T (p.Gln684Ter)

Gene:

SALL1:spalt like transcription factor 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q12.1

Genomic location:

Preferred name:

NM_002968.3(SALL1):c.2050C>T (p.Gln684Ter)

HGVS:

NC_000016.10:g.51140172G>A
NG_007990.1:g.16101C>T
NM_001127892.2:c.1759C>T
NM_002968.3:c.2050C>TMANE SELECT
NP_001121364.1:p.Gln587Ter
NP_002959.2:p.Gln684Ter
LRG_674t1:c.2050C>T
LRG_674:g.16101C>T
NC_000016.9:g.51174083G>A
NM_002968.2:c.2050C>T

Protein change:

Q587*

Links:

dbSNP: rs1597229404

NCBI 1000 Genomes Browser:

rs1597229404

Molecular consequence:

NM_001127892.2:c.1759C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_002968.3:c.2050C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Townes-Brocks syndrome 1 (TBS1)
Synonyms:: DEAFNESS, SENSORINEURAL, WITH IMPERFORATE ANUS AND THUMB ANOMALIES; Renal-ear-anal-radial syndrome; Anus, imperforate, with hand, foot and ear anomalies; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0054581; MedGen: C4551481; Orphanet: 857; OMIM: 107480

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001192748	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	no assertion criteria provided	Likely pathogenic (Jun 28, 2019)	germline	clinical testing
SCV001529266	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 7, 2018)	paternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005086043	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 8, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20301618, 32656166, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001192748

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

no assertion criteria provided

Likely pathogenic
(Jun 28, 2019)

germline

clinical testing

SCV001529266

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 7, 2018)

paternal

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV005086043

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 8, 2024)

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	paternal	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

SALL1-Related Townes-Brocks Syndrome..

Graziano C, Olivucci G.

2007 Jan 24 [updated 2024 Aug 8]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 20301618

A Genetics-First Approach Revealed Monogenic Disorders in Patients With ARM and VACTERL Anomalies.

van de Putte R, Dworschak GC, Brosens E, Reutter HM, Marcelis CLM, Acuna-Hidalgo R, Kurtas NE, Steehouwer M, Dunwoodie SL, Schmiedeke E, Märzheuser S, Schwarzer N, Brooks AS, de Klein A, Sloots CEJ, Tibboel D, Brisighelli G, Morandi A, Bedeschi MF, Bates MD, Levitt MA, Peña A, et al.

Front Pediatr. 2020;8:310. doi: 10.3389/fped.2020.00310.

PubMed [citation]

PMID:: 32656166
PMCID:: PMC7324789

See all PubMed Citations (3)

Details of each submission

From Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare, SCV001192748.1

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

From Baylor Genetics, SCV001529266.1

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

Description

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086043.2

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

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Townes-Brocks syndrome (MIM#107480) and Townes-Brocks branchiootorenal-like syndrome (MIM#107480). NMD escape has been demonstrated for a single PTC in the 5' end of exon 2, where dominant negative or gain of function is a suggested mechanism (PMID: 20301618). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Pathogenic variants within the 5' end exon 2 hot spot region appear to be associated with a more severe outcome than pathogenic variants towards the 3' end in exon 2 (PMID: 20301618). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in a heterozygous individual with Townes-Brocks syndrome (PMID: 32656166). This variant has also been reported as likely pathogenic and VUS in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1204 - This variant has been shown to be de novo in the proband (parental status confirmed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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

Last Updated: Nov 24, 2024

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