VCV000252929.64 - ClinVar

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

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

17 out of 26 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 252929 Accession: VCV000252929.64

Type and length

Deletion, 4 bp

Location

Cytogenetic: 21q22.11 21: 33554982-33554985 (GRCh38) [ NCBI UCSC ] 21: 34927288-34927291 (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	Nov 5, 2016	Apr 20, 2025	Oct 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_138927.4:c.5751_5754del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_138927.4:c.5753_5756del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_620305.3:p.Val1918fs	frameshift
NM_001291411.2:c.5753_5756del	NP_001278340.2:p.Val1918fs	frameshift
NM_001291412.3:c.245-2172_245-2169del		intron variant
NM_032195.3:c.5753_5756del	NP_115571.3:p.Val1918fs	frameshift
NM_138927.2:c.5751_5754delAGTT
NR_103797.2:n.5808_5811del		non-coding transcript variant
NC_000021.9:g.33554984_33554987del
NC_000021.8:g.34927290_34927293del
NG_052981.1:g.16947_16950del

... more HGVS ... less HGVS

Protein change

V1918fs

Other names

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

Canonical SPDI

NC_000021.9:33554981:AGTTAG:AG

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: CA10586132 OMIM: 182465.0001 dbSNP: rs886039773 VarSome

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.
SON		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1543	1631

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.
ZTTK syndrome	Pathogenic (16)	criteria provided, multiple submitters, no conflicts	Mar 7, 2024	RCV000256195.28
Failure to thrive Global developmental delay	Likely pathogenic (1)	criteria provided, single submitter	Jun 21, 2016	RCV000491471.3
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Oct 22, 2021	RCV000624485.7
See cases	Pathogenic (1)	criteria provided, single submitter	Aug 13, 2019	RCV002252062.4
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Oct 1, 2024	RCV001093465.33
Neurodevelopmental abnormality	Pathogenic (1)	no assertion criteria provided	Jun 4, 2020	RCV001264708.4
Hereditary spastic paraplegia 17	Pathogenic (1)	no assertion criteria provided	Oct 25, 2021	RCV001753715.4

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.
Likely pathogenic (Jun 21, 2016) C Contributing to aggregate classification	criteria provided, single submitter (Submitter's publication) Method: clinical testing	Global developmental delay Failure to thrive Developmental delay, failure to (more...) (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Baylor Genetics Study: SON Accession: SCV000297721.1 First in ClinVar: Jun 25, 2017 Last updated: Jun 25, 2017	Publications: PubMed (1) PubMed: 27545676
Pathogenic (Mar 01, 2021) C Contributing to aggregate classification	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	ZTTK syndrome Affected status: yes Allele origin: de novo	New York Genome Center Study: CSER-NYCKidSeq Accession: SCV002099431.1 First in ClinVar: Feb 26, 2022 Last updated: Feb 26, 2022	Comment: 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 … (more) 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. (less) Clinical Features: Global developmental delay (present) , Frontal bossing (present) , Fetal growth restriction (present) , Hypotonia (present) , Failure to thrive (present) , Absent speech (present) Zygosity: Single Heterozygote Secondary finding: no
Pathogenic (Aug 13, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	See cases Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002523222.1 First in ClinVar: Jun 09, 2022 Last updated: Jun 09, 2022	Comment: ACMG classification criteria: PVS1, PS4, PM2, PM6 Clinical Features: Cryptorchidism (present) , Hypermetropia (present) , Triangular face (present) , Short stature (present) , Seizure (present) , Neurodevelopmental abnormality (present) , Generalized hypotonia (present) , Abnormal heart morphology (present) Geographic origin: Brazil
Pathogenic (Jun 29, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ZTTK syndrome Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002549845.1 First in ClinVar: Jul 23, 2022 Last updated: Jul 23, 2022	Comment: _x000D_ Criteria applied: PVS1, PS2_VSTR, PS4, PM2_SUP, PP4
Pathogenic (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ZTTK syndrome Affected status: yes Allele origin: de novo	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille Accession: SCV002559191.1 First in ClinVar: Aug 15, 2022 Last updated: Aug 15, 2022
Pathogenic (Sep 15, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ZTTK syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Breda Genetics srl Accession: SCV002587823.1 First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022	Comment: The variant in c.5753_5756del (p.Val1918Glufs87) in SON gene is reported as pathogenic/likely pathogenic for ZTTK syndrome in ClinVar (Variation ID: 252929) and pathogenic in the … (more) The variant in c.5753_5756del (p.Val1918Glufs87) 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. (less) Zygosity: Single Heterozygote
Pathogenic (Nov 14, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ZTTK syndrome Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV003799164.2 First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023	Comment: PVS1, PS2, PS4, PM2
Pathogenic (Feb 03, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ZTTK syndrome Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003807443.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PM6 strong Number of individuals with the variant: 1 Clinical Features: Median cleft lip and palate (present) , Delayed ability to walk (present) , Maternal hypertension (present) , Neonatal respiratory distress (present) , Penile hypospadias (present) , Cleft upper lip (present) , Hypospadias (present) , Premature birth (present) , Spasticity (present) , Cleft maxillary alveolus (present) , Secondary microcephaly (present) , Severe global developmental delay (present) , Microcephaly (present) , Cleft palate (present) , Strabismus (present) , Delayed fine motor development (present) , 1-2 finger cutaneous syndactyly (present) , Global developmental delay (present) , Delayed ability to stand (present) , Gastrostomy tube feeding in infancy (present) , Delayed gross motor development (present) , Spastic tetraparesis (present) , Absent speech (present) , Delayed speech and language development (present) , Finger syndactyly (present) , Seizure (present) , Intellectual disability, severe (present) , Premature birth following premature rupture of fetal membranes (present) , Median cleft palate (present) , Multifocal seizures (present) , Delayed ability to sit (present) , Median cleft upper lip (present) , Concomitant strabismus (present) , Abnormal atrial septum morphology (present) Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (Feb 22, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ZTTK syndrome Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV003836169.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
Pathogenic (Apr 20, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	ZTTK syndrome Affected status: yes Allele origin: de novo	Duke University Health System Sequencing Clinic, Duke University Health System Accession: SCV003919009.1 First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023	Publications: PubMed (2) PubMed: 25590979‚ 27545680
Pathogenic (May 02, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	ZTTK syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV003922183.1 First in ClinVar: May 06, 2023 Last updated: May 06, 2023	Comment: 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 … (more) 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). (less)
Pathogenic (Oct 22, 2021) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000741182.6 First in ClinVar: Apr 15, 2018 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 25590979‚ 27256762‚ 27545676‚ 27545680 Comment: The c.5753_5756delTTAG (p.V1918Efs87) alteration, located in exon 3 (coding exon 3) of the SON gene, consists of a deletion of 4 nucleotides from position 5753 … (more) The c.5753_5756delTTAG (p.V1918Efs87) alteration, located in exon 3 (coding exon 3) of the SON gene, consists of a deletion of 4 nucleotides from position 5753 to 5756, causing a translational frameshift with a predicted alternate stop codon after 87 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported as a de novo occurrence in multiple affected individuals (Zhu, 2015; Kim, 2016; Takenouchi, 2016; Tokita, 2016; Ambry internal data). Real-time qPCR showed significantly decreased levels of SON mRNA transcripts in peripheral blood from two individuals harboring this variant, as compared to unaffected individuals negative for the variant (Kim, 2016). Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Oct 01, 2024) C Contributing to aggregate classification	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: SCV002181052.4 First in ClinVar: Mar 28, 2022 Last updated: Feb 25, 2025	Publications: PubMed (2) PubMed: 27545676‚ 27545680 Comment: This sequence change creates a premature translational stop signal (p.Val1918Glufs87) in the SON gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Val1918Glufs87) in the SON gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SON are known to be pathogenic (PMID: 27545676, 27545680). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Zhu-Tokita-Takenouchi-Kim syndrome (PMID: 27545676, 27545680). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 252929). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 07, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ZTTK syndrome Affected status: yes Allele origin: germline	3billion Accession: SCV005904047.1 First in ClinVar: Apr 13, 2025 Last updated: Apr 13, 2025	Publications: PubMed (1) PubMed: 25590979 Comment: The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function … (more) The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000252929 /PMID: 25590979 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Pathogenic (Dec 12, 2018) C Contributing to aggregate classification	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	ZTTK syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV001150266.2 First in ClinVar: Feb 03, 2020 Last updated: Apr 13, 2025	Zygosity: Single Heterozygote Sex: male Tissue: blood
Pathogenic (May 31, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ZTTK syndrome Affected status: yes Allele origin: de novo	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV002568429.2 First in ClinVar: Sep 03, 2022 Last updated: Apr 13, 2025	Number of individuals with the variant: 1 Clinical Features: Hypospadias (present) , Unilateral renal agenesis (present) , Deeply set eye (present) , Myopia (present) , Thick eyebrow (present) , Synophrys (present) , Hypothyroidism (present) , Primary hypothyroidism (present) , Visual field defect (present) , Intellectual disability (present) , Seizure (present) , Global developmental delay (present) , Gait disturbance (present) , Ventricular septal defect (present) , Pes planus (present) , Vomiting (present) , Cerebral atrophy (present) , Asthma (present) , Ventriculomegaly (present) , Abnormal speech pattern (present) , Resting tremor (present) , Attention deficit hyperactivity disorder (present) , Myopic astigmatism (present) Zygosity: Single Heterozygote Age: 10-19 years Sex: male Tissue: blood
Pathogenic (Jun 01, 2024) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001250472.29 First in ClinVar: May 12, 2020 Last updated: Apr 20, 2025	Comment: SON: PM6:Very Strong, PVS1, PM2, PS4:Moderate Number of individuals with the variant: 5
Likely pathogenic (Sep 01, 2016) N Not contributing to aggregate classification	no assertion criteria provided Method: research	ZTTK syndrome Affected status: yes Allele origin: unknown	University of Washington Center for Mendelian Genomics, University of Washington Accession: SCV000883002.1 First in ClinVar: Nov 10, 2016 Last updated: Nov 10, 2016	Publications: PubMed (1) PubMed: 27545680 Zygosity: Single Heterozygote
Pathogenic (Jun 19, 2020) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	ZTTK syndrome Affected status: yes Allele origin: de novo	Service de Génétique Moléculaire, Hôpital Robert Debré Accession: SCV001450712.1 First in ClinVar: Dec 19, 2020 Last updated: Dec 19, 2020
Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001968199.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Pathogenic (Oct 25, 2021) N Not contributing to aggregate classification	no assertion criteria provided (ACMG Guidelines, 2022) Method: clinical testing	Hereditary spastic paraplegia 17 Affected status: yes Allele origin: de novo	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV001994791.1 First in ClinVar: Nov 06, 2021 Last updated: Nov 06, 2021
Pathogenic (Jan 15, 2015) N Not contributing to aggregate classification	no assertion criteria provided Method: literature only	ZTTK SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000322738.3 First in ClinVar: Oct 14, 2016 Last updated: Dec 03, 2022	Publications: PubMed (5) PubMed: 25590979‚ 27256762‚ 27545676‚ 27545680‚ 34521999 Comment on evidence: 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) … (more) 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. (less)
Pathogenic (Jan 14, 2021) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: de novo	Molecular Genetics laboratory, Necker Hospital Accession: SCV004031366.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023	Clinical Features: Intellectual disability (present)
Pathogenic (Jun 04, 2020) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Neurodevelopmental abnormality Affected status: yes Allele origin: de novo	Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine Accession: SCV001442891.2 First in ClinVar: Nov 12, 2020 Last updated: Apr 13, 2025	Sex: female
Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001741052.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
not provided (-) N Not contributing to aggregate classification	no classification provided Method: phenotyping only	ZTTK syndrome Affected status: yes Allele origin: unknown	GenomeConnect - Brain Gene Registry Accession: SCV003931201.2 First in ClinVar: Jun 17, 2023 Last updated: Apr 13, 2025	Comment: 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 … (more) 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/. (less) Clinical Features: Hearing impairment (present) , Failure to thrive (present) , Intermittent diarrhea (present) , Pyelonephritis (present) , Global developmental delay (present) , Immunodeficiency (present) Indication for testing: Diagnostic Zygosity: Single Heterozygote Age: 0-9 years Sex: female Method: Exome Sequencing Testing laboratory: Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Date variant was reported to submitter: 2017-03-16 Testing laboratory interpretation: Pathogenic
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Comment:

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.

Comment:

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.

Comment:

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).

Comment:

The c.5753_5756delTTAG (p.V1918Efs*87) alteration, located in exon 3 (coding exon 3) of the SON gene, consists of a deletion of 4 nucleotides from position 5753 to 5756, causing a translational frameshift with a predicted alternate stop codon after 87 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported as a de novo occurrence in multiple affected individuals (Zhu, 2015; Kim, 2016; Takenouchi, 2016; Tokita, 2016; Ambry internal data). Real-time qPCR showed significantly decreased levels of SON mRNA transcripts in peripheral blood from two individuals harboring this variant, as compared to unaffected individuals negative for the variant (Kim, 2016). Based on the available evidence, this alteration is classified as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Val1918Glufs*87) in the SON gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SON are known to be pathogenic (PMID: 27545676, 27545680). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Zhu-Tokita-Takenouchi-Kim syndrome (PMID: 27545676, 27545680). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 252929). For these reasons, this variant has been classified as Pathogenic.

Comment:

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000252929 /PMID: 25590979 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

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/.

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
Establishing the phenotypic spectrum of ZTTK syndrome by analysis of 52 individuals with variants in SON.	Dingemans AJM	European journal of human genetics : EJHG	2022	PMID: 34521999
De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome.	Kim JH	American journal of human genetics	2016	PMID: 27545680
De Novo Truncating Variants in SON Cause Intellectual Disability, Congenital Malformations, and Failure to Thrive.	Tokita MJ	American journal of human genetics	2016	PMID: 27545676
Establishing SON in 21q22.11 as a cause a new syndromic form of intellectual disability: Possible contribution to Braddock-Carey syndrome phenotype.	Takenouchi T	American journal of medical genetics. Part A	2016	PMID: 27256762
Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios.	Zhu X	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25590979

Text-mined citations for rs886039773 ...

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 Apr 20, 2025

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs886039773 ...