NM_001365902.3(NFIX):c.413del (p.Lys138fs) AND Malan overgrowth syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 24, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002810023.3

Allele description [Variation Report for NM_001365902.3(NFIX):c.413del (p.Lys138fs)]

NM_001365902.3(NFIX):c.413del (p.Lys138fs)

Gene:

NFIX:nuclear factor I X [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

19p13.13

Genomic location:

Preferred name:

NM_001365902.3(NFIX):c.413del (p.Lys138fs)

Other names:

NM_001378405.1:c.461del

HGVS:

NC_000019.10:g.13025406del
NG_032925.2:g.34637del
NG_140480.1:g.618del
NM_001271043.2:c.437del
NM_001271044.3:c.389del
NM_001365902.3:c.413delMANE SELECT
NM_001365982.2:c.413del
NM_001365983.2:c.272del
NM_001365984.2:c.410del
NM_001365985.2:c.410del
NM_001378404.1:c.389del
NM_001378405.1:c.461del
NM_002501.4:c.413del
NP_001257972.1:p.Lys146fs
NP_001257973.1:p.Lys130fs
NP_001352831.1:p.Lys138fs
NP_001352911.1:p.Lys138fs
NP_001352912.1:p.Lys91fs
NP_001352913.1:p.Lys137fs
NP_001352914.1:p.Lys137fs
NP_001365333.1:p.Lys130fs
NP_001365334.1:p.Lys154fs
NP_002492.2:p.Lys138fs
NC_000019.9:g.13136220del

Protein change:

K130fs

Molecular consequence:

NM_001271043.2:c.437del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001271044.3:c.389del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001365902.3:c.413del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001365982.2:c.413del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001365983.2:c.272del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001365984.2:c.410del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001365985.2:c.410del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001378404.1:c.389del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001378405.1:c.461del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_002501.4:c.413del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Malan overgrowth syndrome (MALNS)
Synonyms:: Sotos syndrome 2; MALAN SYNDROME
Identifiers:: MONDO: MONDO:0013885; MedGen: C3553660; Orphanet: 420179; OMIM: 614753

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003761208	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 24, 2023)	germline	curation	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003761208

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 24, 2023)

germline

curation

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV003761208.1

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

Description

The heterozygous p.Lys138fs variant in NFIX was identified by our study in one individual with Malan syndrome. Trio exome analysis showed this variant to be de novo. The p.Lys138fs variant in NFIX has not been previously reported in individuals with Malan syndrome. 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 138 and leads to a premature termination codon 73 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the NFIX gene is an established disease mechanism in Malan syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Malan syndrome. ACMG/AMP Criteria applied: PVS1, PS2, 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

Last Updated: Jun 23, 2024

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