NM_052867.4(NALCN):c.965T>C (p.Ile322Thr) AND Inborn genetic diseases

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 8, 2022
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:: RCV002521493.4

Allele description [Variation Report for NM_052867.4(NALCN):c.965T>C (p.Ile322Thr)]

NM_052867.4(NALCN):c.965T>C (p.Ile322Thr)

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.965T>C (p.Ile322Thr)

HGVS:

NC_000013.11:g.101292072A>G
NG_053176.1:g.130135T>C
NM_001350748.2:c.965T>C
NM_001350749.2:c.965T>C
NM_001350750.2:c.965T>C
NM_001350751.2:c.965T>C
NM_052867.4:c.965T>CMANE SELECT
NP_001337677.1:p.Ile322Thr
NP_001337678.1:p.Ile322Thr
NP_001337679.1:p.Ile322Thr
NP_001337680.1:p.Ile322Thr
NP_443099.1:p.Ile322Thr
NC_000013.10:g.101944423A>G
NM_052867.2:c.965T>C

Protein change:

I322T

Links:

dbSNP: rs1057519433

NCBI 1000 Genomes Browser:

rs1057519433

Molecular consequence:

NM_001350748.2:c.965T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001350749.2:c.965T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001350750.2:c.965T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001350751.2:c.965T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_052867.4:c.965T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Inborn genetic diseases
Identifiers:: MeSH: D030342; MedGen: C0950123

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003748506	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Feb 8, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27473021, 28327206 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003748506

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Feb 8, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

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	clinical testing

Citations

PubMed

Muscle biopsy findings in a child with NALCN gene mutation.

Sivaraman I, Friedman NR, Prayson RA.

J Clin Neurosci. 2016 Dec;34:222-223. doi: 10.1016/j.jocn.2016.06.018. Epub 2016 Jul 26.

PubMed [citation]

PMID:: 27473021

Lessons learned from additional research analyses of unsolved clinical exome cases.

Eldomery MK, Coban-Akdemir Z, Harel T, Rosenfeld JA, Gambin T, Stray-Pedersen A, Küry S, Mercier S, Lessel D, Denecke J, Wiszniewski W, Penney S, Liu P, Bi W, Lalani SR, Schaaf CP, Wangler MF, Bacino CA, Lewis RA, Potocki L, Graham BH, Belmont JW, et al.

Genome Med. 2017 Mar 21;9(1):26. doi: 10.1186/s13073-017-0412-6.

PubMed [citation]

PMID:: 28327206
PMCID:: PMC5361813

Details of each submission

From Ambry Genetics, SCV003748506.2

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

Description

The c.965T>C (p.I322T) alteration is located in exon 9 (coding exon 8) of the NALCN gene. This alteration results from a T to C substitution at nucleotide position 965, causing the isoleucine (I) at amino acid position 322 to be replaced by a threonine (T). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was reported de novo in a child with congenital arthrogryposis, global developmental delay, hypotonia, feeding difficulties, visual deficits, possible seizures, and dysmorphic features (Sivaraman, 2016). This alteration has also been identified in two patients reported to have a similar neurodevelopmental disorder (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely 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

Last Updated: Oct 20, 2024

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