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NM_052867.4(NALCN):c.537del (p.Ile178_Trp179insTer) AND Hypotonia, infantile, with psychomotor retardation and characteristic facies 1

Germline classification:
Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:
Jan 25, 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:
RCV000845228.5

Allele description [Variation Report for NM_052867.4(NALCN):c.537del (p.Ile178_Trp179insTer)]

NM_052867.4(NALCN):c.537del (p.Ile178_Trp179insTer)

Gene:
NALCN:sodium leak channel, non-selective [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
13q33.1
Genomic location:
Preferred name:
NM_052867.4(NALCN):c.537del (p.Ile178_Trp179insTer)
Other names:
NM_052867.4(NALCN):c.537del; p.Ile178_Trp179insTer
HGVS:
  • NC_000013.11:g.101376808del
  • NG_053176.1:g.45400del
  • NM_001350748.2:c.537del
  • NM_001350749.2:c.537del
  • NM_001350750.2:c.537del
  • NM_001350751.2:c.537del
  • NM_052867.4:c.537delMANE SELECT
  • NP_001337677.1:p.Ile178_Trp179insTer
  • NP_001337678.1:p.Ile178_Trp179insTer
  • NP_001337679.1:p.Ile178_Trp179insTer
  • NP_001337680.1:p.Ile178_Trp179insTer
  • NP_443099.1:p.Ile178_Trp179insTer
  • NC_000013.10:g.102029159del
  • NM_052867.2:c.537delG
Links:
dbSNP: rs1594759803
NCBI 1000 Genomes Browser:
rs1594759803
Molecular consequence:
  • NM_001350748.2:c.537del - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001350749.2:c.537del - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001350750.2:c.537del - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001350751.2:c.537del - nonsense - [Sequence Ontology: SO:0001587]
  • NM_052867.4:c.537del - nonsense - [Sequence Ontology: SO:0001587]
Observations:
1

Condition(s)

Name:
Hypotonia, infantile, with psychomotor retardation and characteristic facies 1 (INNFD)
Identifiers:
MONDO: MONDO:0024567; MedGen: C3809454; Orphanet: 371364; OMIM: 615419

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000987164Yale Center for Mendelian Genomics, Yale University
no assertion criteria provided
Pathogenic
(Aug 23, 2018) 		germlineliterature only

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

SCV0025730313billion
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Sep 1, 2022) 		germlineclinical testing

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

SCV003761326Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Jan 25, 2023) 		germlinecuration

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot provided1not providedliterature only, clinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Citations

PubMed

Genetic variants in components of the NALCN-UNC80-UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies).

Bramswig NC, Bertoli-Avella AM, Albrecht B, Al Aqeel AI, Alhashem A, Al-Sannaa N, Bah M, Bröhl K, Depienne C, Dorison N, Doummar D, Ehmke N, Elbendary HM, Gorokhova S, Héron D, Horn D, James K, Keren B, Kuechler A, Ismail S, Issa MY, Marey I, et al.

Hum Genet. 2018 Sep;137(9):753-768. doi: 10.1007/s00439-018-1929-5. Epub 2018 Aug 23.

PubMed [citation]
PMID:
30167850
PMCID:
PMC6671679

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 Yale Center for Mendelian Genomics, Yale University, SCV000987164.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedliterature only PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

From 3billion, SCV002573031.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (2)

Description

The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with NALCN-related disorder (ClinVar ID: VCV000684711 / PMID: 30167850). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV003761326.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (1)

Description

The homozygous p.Trp179fsTer1 variant in NALCN was identified by our study in one individual with microcephaly, seizures, and global developmental delay. The p.Trp179fsTer1 variant in NALCN has been previously reported in 2 individuals with infantile hypotonia with psychomotor retardation and characteristic facies 1 (PMID: 30167850, SCV002573031.1). These 2 affected individuals were homozygotes, which increases the likelihood that the p.Trp179fsTer1 variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 684711) and has been interpreted as pathogenic by 3billion and the Yale Center for Mendelian Genomics. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 179 and leads to a premature termination codon 1 amino acid downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the NALCN gene is strongly associated to autosomal recessive infantile hypotonia with psychomotor retardation and characteristic facies 1. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive infantile hypotonia with psychomotor retardation and characteristic facies 1. ACMG/AMP Criteria applied: PVS1_Strong, PM2_Supporting, PM3 (Richards 2015).

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

Last Updated: Jun 23, 2024