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NM_052867.4(NALCN):c.1519G>T (p.Gly507Trp) AND not provided

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Oct 7, 2020
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:
RCV004018123.1

Allele description [Variation Report for NM_052867.4(NALCN):c.1519G>T (p.Gly507Trp)]

NM_052867.4(NALCN):c.1519G>T (p.Gly507Trp)

Gene:
NALCN:sodium leak channel, non-selective [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
13q33.1
Genomic location:
Preferred name:
NM_052867.4(NALCN):c.1519G>T (p.Gly507Trp)
HGVS:
  • NC_000013.11:g.101229500C>A
  • NG_053176.1:g.192707G>T
  • NM_001350748.2:c.1519G>T
  • NM_001350749.2:c.1519G>T
  • NM_001350750.2:c.1432G>T
  • NM_001350751.2:c.1432G>T
  • NM_052867.4:c.1519G>TMANE SELECT
  • NP_001337677.1:p.Gly507Trp
  • NP_001337678.1:p.Gly507Trp
  • NP_001337679.1:p.Gly478Trp
  • NP_001337680.1:p.Gly478Trp
  • NP_443099.1:p.Gly507Trp
  • NC_000013.10:g.101881851C>A
Protein change:
G478W
Molecular consequence:
  • NM_001350748.2:c.1519G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001350749.2:c.1519G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001350750.2:c.1432G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001350751.2:c.1432G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_052867.4:c.1519G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004848385Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(Oct 7, 2020) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Additional de novo missense genetic variants in NALCN associated with CLIFAHDD syndrome.

Vivero M, Cho MT, Begtrup A, Wentzensen IM, Walsh L, Payne K, Zarate YA, Bosanko K, Schaefer GB, DeBrosse S, Pollack L, Mason K, Retterer K, DeWard S, Juusola J, Chung WK.

Clin Genet. 2017 Jun;91(6):929-931. doi: 10.1111/cge.12899. Epub 2017 Jan 30. No abstract available.

PubMed [citation]
PMID:
28133733

A de novo mutation in the NALCN gene in an adult patient with cerebellar ataxia associated with intellectual disability and arthrogryposis.

Wang Y, Koh K, Ichinose Y, Yasumura M, Ohtsuka T, Takiyama Y.

Clin Genet. 2016 Dec;90(6):556-557. doi: 10.1111/cge.12851. Epub 2016 Sep 16. No abstract available.

PubMed [citation]
PMID:
27633718
See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848385.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

The p.Gly507Trp variant in NALCN has not been previously reported in individuals with NALCN-related neurological disease and was absent from large population studies. This variant was confirmed to be de novo in an individual with intellectual disability, adult-onset progressive ataxia, speech changes, tremor, and cognitive regression by the Broad Institute Rare Genomes Project. However, given the differences in phenotypic presentation between this individual and individuals in the literature with disease-causing variants in NALCN, the significance of this de novo occurrence is uncertain. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in this region of the NALCN gene in the general population is lower than expected, suggesting that a missense variant in this region may not be tolerated. In summary, while there is some suspicion that this variant may cause autosomal dominant NALCN-related neurological disease, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS2_Moderate, PM2_Supporting, PP2, PP3.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 1, 2024