NM_020928.2(ZSWIM6):c.2737C>T (p.Arg913Ter) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 31, 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:: RCV000760560.11

Allele description [Variation Report for NM_020928.2(ZSWIM6):c.2737C>T (p.Arg913Ter)]

NM_020928.2(ZSWIM6):c.2737C>T (p.Arg913Ter)

Gene:

ZSWIM6:zinc finger SWIM-type containing 6 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q12.1

Genomic location:

Preferred name:

NM_020928.2(ZSWIM6):c.2737C>T (p.Arg913Ter)

HGVS:

NC_000005.10:g.61541917C>T
NG_053150.1:g.214645C>T
NM_020928.2:c.2737C>TMANE SELECT
NP_065979.1:p.Arg913Ter
NC_000005.9:g.60837744C>T
NM_020928.1:c.2737C>T

Protein change:

R913*; ARG913TER

Links:

OMIM: 615951.0002; dbSNP: rs1554041295

NCBI 1000 Genomes Browser:

rs1554041295

Molecular consequence:

NM_020928.2:c.2737C>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
SCV000890451	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jan 31, 2023)	germline	clinical testing	Citation Link,
SCV000958315	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 4, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29198722, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000890451

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jan 31, 2023)

germline

clinical testing

Citation Link,

SCV000958315

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 4, 2018)

germline

clinical testing

PubMed (2)
[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

A Recurrent De Novo Nonsense Variant in ZSWIM6 Results in Severe Intellectual Disability without Frontonasal or Limb Malformations.

Palmer EE, Kumar R, Gordon CT, Shaw M, Hubert L, Carroll R, Rio M, Murray L, Leffler M, Dudding-Byth T, Oufadem M, Lalani SR, Lewis AM, Xia F, Tam A, Webster R, Brammah S, Filippini F, Pollard J, Spies J, Minoche AE, Cowley MJ, et al.

Am J Hum Genet. 2017 Dec 7;101(6):995-1005. doi: 10.1016/j.ajhg.2017.10.009. Epub 2017 Nov 30.

PubMed [citation]

PMID:: 29198722
PMCID:: PMC5812890

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From GeneDx, SCV000890451.4

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

Description

Published functional studies demonstrate a dominant-negative effect on the protein (Palmer et al., 2017); Not observed in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation as the last 303 amino acids are lost; This variant is associated with the following publications: (PMID: 29198722, 33958584, 34758253)

#	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, SCV000958315.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change creates a premature translational stop signal (p.Arg913*) in the ZSWIM6 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in ZSWIM6 cause disease. This variant has been observed to be likely or confirmed de novo in multiple individuals affected with severe-profound intellectual disability/developmental delay and additional neurological features, but without frontonasal or limb malformations¬†(PMID: 29198722, Invitae). ClinVar contains an entry for this variant (Variation ID:¬†431797). Experimental studies have shown that this nonsense change does not trigger nonsense-mediated decay of the ZSWIM6 mRNA. This suggests a truncated ZSWIM6 protein lacking the Sin3-like domain exists, which may have a dominant-negative effect.¬†(PMID: 29198722).

#	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: Mar 10, 2024

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