NM_022455.5(NSD1):c.1810C>T (p.Arg604Ter) AND Sotos syndrome

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Nov 22, 2022
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:: RCV003231175.9

Allele description [Variation Report for NM_022455.5(NSD1):c.1810C>T (p.Arg604Ter)]

NM_022455.5(NSD1):c.1810C>T (p.Arg604Ter)

Gene:

NSD1:nuclear receptor binding SET domain protein 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q35.3

Genomic location:

Preferred name:

NM_022455.5(NSD1):c.1810C>T (p.Arg604Ter)

HGVS:

NC_000005.10:g.177210209C>T
NG_009821.1:g.82131C>T
NM_001365684.2:c.937C>T
NM_001409301.1:c.1810C>T
NM_001409302.1:c.1810C>T
NM_001409303.1:c.1810C>T
NM_001409304.1:c.1390C>T
NM_001409305.1:c.1057C>T
NM_001409306.1:c.937C>T
NM_001409307.1:c.937C>T
NM_001409308.1:c.937C>T
NM_001409309.1:c.937C>T
NM_022455.5:c.1810C>TMANE SELECT
NM_172349.5:c.937C>T
NP_001352613.1:p.Arg335Ter
NP_001352613.2:p.Arg313Ter
NP_001396230.1:p.Arg604Ter
NP_001396231.1:p.Arg604Ter
NP_001396232.1:p.Arg604Ter
NP_001396233.1:p.Arg464Ter
NP_001396234.1:p.Arg353Ter
NP_001396235.1:p.Arg313Ter
NP_001396236.1:p.Arg313Ter
NP_001396237.1:p.Arg313Ter
NP_001396238.1:p.Arg313Ter
NP_071900.2:p.Arg604Ter
NP_071900.2:p.Arg604Ter
NP_758859.1:p.Arg335Ter
NP_758859.2:p.Arg313Ter
LRG_512t1:c.1810C>T
LRG_512:g.82131C>T
LRG_512p1:p.Arg604Ter
NC_000005.9:g.176637210C>T
NM_001365684.1:c.1003C>T
NM_022455.4:c.1810C>T
NM_172349.3:c.1003C>T

Protein change:

R313*

Links:

dbSNP: rs587784076

NCBI 1000 Genomes Browser:

rs587784076

Molecular consequence:

NM_001365684.2:c.937C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001409301.1:c.1810C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001409302.1:c.1810C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001409303.1:c.1810C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001409304.1:c.1390C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001409305.1:c.1057C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001409306.1:c.937C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001409307.1:c.937C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001409308.1:c.937C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001409309.1:c.937C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_022455.5:c.1810C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_172349.5:c.937C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Sotos syndrome (SOTOS)
Synonyms:: Sotos' syndrome; Cerebral gigantism; Distinctive facial appearance, overgrowth in childhood, and learning disabilities or delayed development; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0019349; MedGen: C0175695; Orphanet: 821; OMIM: 117550

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000194094	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2007)	Pathogenic (Feb 8, 2013)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001579158	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 14, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 14571271, 16247291, 12464997, 15942875, 19876911, 28492532
SCV002054913	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003935088	Eurofins-Biomnis	criteria provided, single submitter (Accession Criteria ClinVar Biomnis)	Pathogenic (Nov 22, 2022)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	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
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007.

Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR, Lyon E, Ward BE; Molecular Subcommittee of the ACMG Laboratory Quality Assurance Committee..

Genet Med. 2008 Apr;10(4):294-300. doi: 10.1097/GIM.0b013e31816b5cae.

PubMed [citation]

PMID:: 18414213

Mutations in NSD1 are responsible for Sotos syndrome, but are not a frequent finding in other overgrowth phenotypes.

Türkmen S, Gillessen-Kaesbach G, Meinecke P, Albrecht B, Neumann LM, Hesse V, Palanduz S, Balg S, Majewski F, Fuchs S, Zschieschang P, Greiwe M, Mennicke K, Kreuz FR, Dehmel HJ, Rodeck B, Kunze J, Tinschert S, Mundlos S, Horn D.

Eur J Hum Genet. 2003 Nov;11(11):858-65.

PubMed [citation]

PMID:: 14571271

See all PubMed Citations (8)

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV000194094.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV001579158.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change creates a premature translational stop signal (p.Arg604*) in the NSD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NSD1 are known to be pathogenic (PMID: 12464997, 14571271, 15942875, 16247291). This variant is not present in population databases (ExAC no frequency). This premature translational stop signal has been observed in individual(s) with Sotos syndrome (PMID: 12464997, 15942875, 19876911). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic.

#	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 Genome-Nilou Lab, SCV002054913.1

#	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	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Eurofins-Biomnis, SCV003935088.1

#	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	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Jun 9, 2024

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