NM_052867.4(NALCN):c.3064A>G (p.Ile1022Val) AND Congenital contractures of the limbs and face, hypotonia, and developmental delay

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Feb 23, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000622774.5

Allele description [Variation Report for NM_052867.4(NALCN):c.3064A>G (p.Ile1022Val)]

NM_052867.4(NALCN):c.3064A>G (p.Ile1022Val)

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.3064A>G (p.Ile1022Val)

HGVS:

NC_000013.11:g.101100882T>C
NG_053176.1:g.321325A>G
NM_001350748.2:c.3151A>G
NM_001350749.2:c.3064A>G
NM_001350750.2:c.2977A>G
NM_001350751.2:c.2977A>G
NM_052867.4:c.3064A>GMANE SELECT
NP_001337677.1:p.Ile1051Val
NP_001337678.1:p.Ile1022Val
NP_001337679.1:p.Ile993Val
NP_001337680.1:p.Ile993Val
NP_443099.1:p.Ile1022Val
NC_000013.10:g.101753233T>C
NM_052867.3:c.3064A>G

Protein change:

I1022V

Links:

dbSNP: rs1555381108

NCBI 1000 Genomes Browser:

rs1555381108

Molecular consequence:

NM_001350748.2:c.3151A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001350749.2:c.3064A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001350750.2:c.2977A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001350751.2:c.2977A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_052867.4:c.3064A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD)
Identifiers:: MONDO: MONDO:0014556; MedGen: C4225398; OMIM: 616266

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000740312	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 22, 2018)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003841445	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 23, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000740312

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 22, 2018)

de novo

clinical testing

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

SCV003841445

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 23, 2023)

unknown

clinical testing

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	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

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 Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues, SCV000740312.1

#	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	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV003841445.1

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

Description

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.61; 3Cnet: 0.37). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with autosomal dominant congenital contractures of the limbs and face, hypotonia, and developmental delay (ClinVar ID: VCV000520429). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 4, 2024

ClinVar

Relating variation to medicine