NM_138927.4(SON):c.5753_5756del (p.Val1918fs) AND ZTTK syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (15 submissions)
Last evaluated:: May 2, 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:: RCV000256195.26

Allele description

NM_138927.4(SON):c.5753_5756del (p.Val1918fs)

Gene:

SON:SON DNA and RNA binding protein [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

21q22.11

Genomic location:

Preferred name:

NM_138927.4(SON):c.5753_5756del (p.Val1918fs)

Other names:

p.V1918Efs*87; NM_138927.4(SON):c.5753_5756del; p.Val1918fs

HGVS:

NC_000021.9:g.33554984_33554987del
NG_052981.1:g.16947_16950del
NM_001291411.2:c.5753_5756del
NM_001291412.3:c.245-2172_245-2169del
NM_032195.3:c.5753_5756del
NM_138927.4:c.5753_5756delMANE SELECT
NP_001278340.2:p.Val1918fs
NP_115571.3:p.Val1918fs
NP_620305.3:p.Val1918fs
NC_000021.8:g.34927288_34927291del
NC_000021.8:g.34927290_34927293del
NM_032195.2:c.5753_5756del
NM_032195.2:c.5753_5756delTTAG
NM_138927.1:c.5753_5756delTTAG
NM_138927.2:c.5751_5754delAGTT
NM_138927.2:c.5753_5756delTTAG
NM_138927.3:c.5753_5756del
NM_138927.4:c.5751_5754delMANE SELECT
NM_138927.4:c.5753_5756del
NR_103797.2:n.5808_5811del

Protein change:

V1918fs

Links:

OMIM: 182465.0001; dbSNP: rs886039773

NCBI 1000 Genomes Browser:

rs886039773

Molecular consequence:

NM_001291411.2:c.5753_5756del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_032195.3:c.5753_5756del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_138927.4:c.5753_5756del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001291412.3:c.245-2172_245-2169del - intron variant - [Sequence Ontology: SO:0001627]
NR_103797.2:n.5808_5811del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: ZTTK syndrome (ZTTKS)
Synonyms:: ZTTK MULTIPLE CONGENITAL ANOMALIES-MENTAL RETARDATION SYNDROME; ZHU-TOKITA-TAKENOUCHI-KIM SYNDROME
Identifiers:: MONDO: MONDO:0014936; MedGen: C4310696; OMIM: 617140

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000322738	OMIM	no assertion criteria provided	Pathogenic (Jan 15, 2015)	germline	literature only	PubMed (5) [See all records that cite these PMIDs] 27256762, 27545676, 25590979, 27545680, 34521999
SCV000883002	University of Washington Center for Mendelian Genomics, University of Washington	no assertion criteria provided	Likely pathogenic (Sep 1, 2016)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV001150266	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Dec 12, 2018)	de novo	clinical testing	Citation Link,
SCV001450712	Service de Génétique Moléculaire, Hôpital Robert Debré	no assertion criteria provided	Pathogenic (Jun 19, 2020)	de novo	clinical testing
SCV002099431	New York Genome Center - CSER-NYCKidSeq	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Pathogenic (Mar 1, 2021)	de novo	clinical testing	Citation Link,
SCV002549845	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 29, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002559191	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002568429	Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 31, 2022)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002587823	Breda Genetics srl	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 15, 2022)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003799164	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 14, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003807443	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 3, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003836169	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 22, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003919009	Duke University Health System Sequencing Clinic, Duke University Health System	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 20, 2023)	de novo	research	PubMed (3) [See all records that cite these PMIDs] 25590979, 27545680, 25741868
SCV003922183	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 2, 2023)	germline	curation	PubMed (1) [See all records that cite this PMID]
SCV003931201	GenomeConnect - Brain Gene Registry	no classification provided	not provided	unknown	phenotyping only

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	4	not provided	not provided	2	not provided	clinical testing, research
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	1	not provided	not provided	1	not provided	clinical testing, research, phenotyping only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Establishing SON in 21q22.11 as a cause a new syndromic form of intellectual disability: Possible contribution to Braddock-Carey syndrome phenotype.

Takenouchi T, Miura K, Uehara T, Mizuno S, Kosaki K.

Am J Med Genet A. 2016 Oct;170(10):2587-90. doi: 10.1002/ajmg.a.37761. Epub 2016 Jun 3.

PubMed [citation]

PMID:: 27256762

De Novo Truncating Variants in SON Cause Intellectual Disability, Congenital Malformations, and Failure to Thrive.

Tokita MJ, Braxton AA, Shao Y, Lewis AM, Vincent M, Küry S, Besnard T, Isidor B, Latypova X, Bézieau S, Liu P, Motter CS, Melver CW, Robin NH, Infante EM, McGuire M, El-Gharbawy A, Littlejohn RO, McLean SD, Bi W, Bacino CA, Lalani SR, et al.

Am J Hum Genet. 2016 Sep 1;99(3):720-727. doi: 10.1016/j.ajhg.2016.06.035. Epub 2016 Aug 18.

PubMed [citation]

PMID:: 27545676
PMCID:: PMC5011061

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000322738.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (5)

Description

In a 5-year-old girl (from trio 91) with ZTTK syndrome (ZTTKS; 617140), Zhu et al. (2015) identified heterozygosity for a de novo 4-bp deletion (ENST00000356577.4:c.5751_5754delAGTT) in the SON gene, resulting in a frameshift and premature termination (Val1918GlufsTer87).

In a 13-year-old boy with ZTTK syndrome, Takenouchi et al. (2016) identified heterozygosity for the same 4-bp deletion (c.5753_5756delTTAG, NM_138927.2) in the SON gene, resulting in a frameshift and premature termination (Val 1918GlufsTer87). The mutation occurred de novo.

Tokita et al. (2016) identified a de novo heterozygous c.5753_5756delTTAG mutation in 2 unrelated girls (patients 1 and 5) with ZTTKS. The mutations were found by whole-exome sequencing; the variant was not found in the ExAC database.

In 4 unrelated children (patients 3, 5, 18, 19) with ZTTK syndrome, including the patient (patient 3) reported by Zhu et al. (2015), Kim et al. (2016) identified heterozygosity for a de novo c.5753_5756delTTAG in exon 3 of the SON gene, resulting in a frameshift and premature termination within the RS domain. The mutation, which occurred de novo in all 4 children, was found by exome sequencing and was not found in over 2,000 control individuals. Peripheral blood cells derived from 2 patients showed significantly decreased levels of mutant transcript, consistent with haploinsufficiency.

In a review of molecular data on 52 patients with ZTTK syndrome, Dingemans et al. (2022) found that the most frequently occurring mutation in the SON gene was c.5753_5756delTTAG, which was found in 13 patients.

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

From University of Washington Center for Mendelian Genomics, University of Washington, SCV000883002.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	research	PubMed (1)

#	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		4	not provided	not provided	not provided

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV001150266.1

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

From Service de Génétique Moléculaire, Hôpital Robert Debré, SCV001450712.1

#	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	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From New York Genome Center - CSER-NYCKidSeq, SCV002099431.1

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

Description

The de novo heterozygous four base-pair deletion c.5753_5756del (p.Val1918GlufsTer87) identified in exon 3 (of 12) of the SON gene alters the wild-type translational reading frame and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant has been previously reported in patients affected with ZTTK syndrome [PMID: 27545676; PMID: 27545680]. The variant has been reported as pathogenic in ClinVar database by multiple independent laboratories [Variation ID:252929]. The variant is absent from the gnomAD database suggesting it is not a common benign variant in the populations represented in the that database. Based on the available evidence, the de novo heterozygous c.5753_5756del (p.Val1918GlufsTer87) variant identified the SON gene is reported as Pathogenic.

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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV002549845.1

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

Description

_x000D_ Criteria applied: PVS1, PS2_VSTR, PS4, PM2_SUP, PP4

#	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 Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille, SCV002559191.1

#	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	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN, SCV002568429.1

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

From Breda Genetics srl, SCV002587823.1

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

Description

The variant in c.5753_5756del (p.Val1918Glufs*87) in SON gene is reported as pathogenic/likely pathogenic for ZTTK syndrome in ClinVar (Variation ID: 252929) and pathogenic in the LOVD database v.3.0. The variant creates a shift in the reading frame which is predicted to result in a premature stop codon 87 amino acids downstream. It is likely to result in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). There is no information on frequency in gnomAD or 1000 Genomes Project. The variant has not been identified in the parents, therefore, it can be concluded that the variant is de novo.

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

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV003799164.2

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

Description

PVS1, PS2, PS4, PM2

#	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 Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV003807443.1

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

Description

ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PM6 strong

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

From Baylor Genetics, SCV003836169.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Duke University Health System Sequencing Clinic, Duke University Health System, SCV003919009.1

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

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

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV003922183.1

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

Description

The heterozygous p.Val1918GlufsTer87 variant in SON was identified by our study in one individual with agenesis of the corpus callosum. Trio exome analysis showed this variant to be de novo. The p.Val1918GlufsTer87 variant in SON has been previously reported in 12 unrelated individuals with ZTTK syndrome (PMID: 34521999, PMID: 27256762, PMID: 27545680, PMID: 27545676) and was found to be de novo in these individuals with confirmed paternity and maternity. The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant has also been reported in ClinVar (Variation ID: 252929) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein‚Äôs amino acid sequence beginning at position 1918 and leads to a premature termination codon 87 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the SON gene is an established disease mechanism in autosomal dominant ZTTK syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ZTTK syndrome. ACMG/AMP Criteria applied: PVS1, PS2_VeryStrong, PS4, PM2_Supporting (Richards 2015).

#	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

From GenomeConnect - Brain Gene Registry, SCV003931201.1

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

Description

Variant classified as Pathogenic and reported on 03-16-2017 by The Children's Hospital of Philadelphia. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.

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

Last Updated: Apr 7, 2025

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