VCV001329987.3 - ClinVar

NM_001037132.4(NRCAM):c.2557C>T (p.Arg853Cys)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001037132.4(NRCAM):c.2557C>T (p.Arg853Cys)

Variation ID: 1329987 Accession: VCV001329987.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.1 7: 108181911 (GRCh38) [ NCBI UCSC ] 7: 107822355 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 10, 2022	May 1, 2024	Feb 27, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001037132.4:c.2557C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001032209.1:p.Arg853Cys	missense
NM_001193582.2:c.2557C>T	NP_001180511.1:p.Arg853Cys	missense
NM_001193583.2:c.2500C>T	NP_001180512.1:p.Arg834Cys	missense
NM_001193584.2:c.2500C>T	NP_001180513.1:p.Arg834Cys	missense
NM_001371119.1:c.2500C>T	NP_001358048.1:p.Arg834Cys	missense
NM_001371122.1:c.2500C>T	NP_001358051.1:p.Arg834Cys	missense
NM_001371123.1:c.2557C>T	NP_001358052.1:p.Arg853Cys	missense
NM_001371124.1:c.2500C>T	NP_001358053.1:p.Arg834Cys	missense
NM_001371125.1:c.2212C>T	NP_001358054.1:p.Arg738Cys	missense
NM_001371126.1:c.2500C>T	NP_001358055.1:p.Arg834Cys	missense
NM_001371127.1:c.2554C>T	NP_001358056.1:p.Arg852Cys	missense
NM_001371128.1:c.2557C>T	NP_001358057.1:p.Arg853Cys	missense
NM_001371129.1:c.2500C>T	NP_001358058.1:p.Arg834Cys	missense
NM_001371130.1:c.2509C>T	NP_001358059.1:p.Arg837Cys	missense
NM_001371131.1:c.2557C>T	NP_001358060.1:p.Arg853Cys	missense
NM_001371132.1:c.2500C>T	NP_001358061.1:p.Arg834Cys	missense
NM_001371133.1:c.2509C>T	NP_001358062.1:p.Arg837Cys	missense
NM_001371134.1:c.2506C>T	NP_001358063.1:p.Arg836Cys	missense
NM_001371135.1:c.2500C>T	NP_001358064.1:p.Arg834Cys	missense
NM_001371136.1:c.2509C>T	NP_001358065.1:p.Arg837Cys	missense
NM_001371137.1:c.1600C>T	NP_001358066.1:p.Arg534Cys	missense
NM_001371138.1:c.2557C>T	NP_001358067.1:p.Arg853Cys	missense
NM_001371139.1:c.2500C>T	NP_001358068.1:p.Arg834Cys	missense
NM_001371140.1:c.2500C>T	NP_001358069.1:p.Arg834Cys	missense
NM_001371141.1:c.2500C>T	NP_001358070.1:p.Arg834Cys	missense
NM_001371142.1:c.2212C>T	NP_001358071.1:p.Arg738Cys	missense
NM_001371143.1:c.2212C>T	NP_001358072.1:p.Arg738Cys	missense
NM_001371144.1:c.2557C>T	NP_001358073.1:p.Arg853Cys	missense
NM_001371145.1:c.2500C>T	NP_001358074.1:p.Arg834Cys	missense
NM_001371146.1:c.2500C>T	NP_001358075.1:p.Arg834Cys	missense
NM_001371147.1:c.2212C>T	NP_001358076.1:p.Arg738Cys	missense
NM_001371148.1:c.2239C>T	NP_001358077.1:p.Arg747Cys	missense
NM_001371149.1:c.2557C>T	NP_001358078.1:p.Arg853Cys	missense
NM_001371150.1:c.2527C>T	NP_001358079.1:p.Arg843Cys	missense
NM_001371151.1:c.2509C>T	NP_001358080.1:p.Arg837Cys	missense
NM_001371152.1:c.2509C>T	NP_001358081.1:p.Arg837Cys	missense
NM_001371153.1:c.2557C>T	NP_001358082.1:p.Arg853Cys	missense
NM_001371154.1:c.2500C>T	NP_001358083.1:p.Arg834Cys	missense
NM_001371155.1:c.2500C>T	NP_001358084.1:p.Arg834Cys	missense
NM_001371156.1:c.2557C>T	NP_001358085.1:p.Arg853Cys	missense
NM_001371157.1:c.2509C>T	NP_001358086.1:p.Arg837Cys	missense
NM_001371158.1:c.2500C>T	NP_001358087.1:p.Arg834Cys	missense
NM_001371159.1:c.2527C>T	NP_001358088.1:p.Arg843Cys	missense
NM_001371160.1:c.2539C>T	NP_001358089.1:p.Arg847Cys	missense
NM_001371161.1:c.2557C>T	NP_001358090.1:p.Arg853Cys	missense
NM_001371162.1:c.2500C>T	NP_001358091.1:p.Arg834Cys	missense
NM_001371163.1:c.2500C>T	NP_001358092.1:p.Arg834Cys	missense
NM_001371164.1:c.2212C>T	NP_001358093.1:p.Arg738Cys	missense
NM_001371165.1:c.2500C>T	NP_001358094.1:p.Arg834Cys	missense
NM_001371166.1:c.2500C>T	NP_001358095.1:p.Arg834Cys	missense
NM_001371167.1:c.2500C>T	NP_001358096.1:p.Arg834Cys	missense
NM_001371168.1:c.2557C>T	NP_001358097.1:p.Arg853Cys	missense
NM_001371169.1:c.2557C>T	NP_001358098.1:p.Arg853Cys	missense
NM_001371170.1:c.2239C>T	NP_001358099.1:p.Arg747Cys	missense
NM_001371171.1:c.2509C>T	NP_001358100.1:p.Arg837Cys	missense
NM_001371172.1:c.2500C>T	NP_001358101.1:p.Arg834Cys	missense
NM_001371173.1:c.2557C>T	NP_001358102.1:p.Arg853Cys	missense
NM_001371174.1:c.2527C>T	NP_001358103.1:p.Arg843Cys	missense
NM_001371175.1:c.2509C>T	NP_001358104.1:p.Arg837Cys	missense
NM_001371176.1:c.2509C>T	NP_001358105.1:p.Arg837Cys	missense
NM_001371177.1:c.2500C>T	NP_001358106.1:p.Arg834Cys	missense
NM_001371178.1:c.2509C>T	NP_001358107.1:p.Arg837Cys	missense
NM_001371179.1:c.2239C>T	NP_001358108.1:p.Arg747Cys	missense
NM_001371180.1:c.2239C>T	NP_001358109.1:p.Arg747Cys	missense
NM_001371181.1:c.2500C>T	NP_001358110.1:p.Arg834Cys	missense
NM_001371182.1:c.2452C>T	NP_001358111.1:p.Arg818Cys	missense
NM_005010.5:c.2509C>T	NP_005001.3:p.Arg837Cys	missense
NR_163867.1:n.3025C>T		non-coding transcript variant
NR_163868.1:n.3025C>T		non-coding transcript variant
NR_163869.1:n.3025C>T		non-coding transcript variant
NR_163870.1:n.3106C>T		non-coding transcript variant
NR_163871.1:n.3104C>T		non-coding transcript variant
NC_000007.14:g.108181911G>A
NC_000007.13:g.107822355G>A
NG_029898.2:g.279807C>T

... more HGVS ... less HGVS

Protein change

R534C, R738C, R747C, R818C, R834C, R836C, R837C, R843C, R847C, R852C, R853C

Other names

Canonical SPDI

NC_000007.14:108181910:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00020 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Exome Aggregation Consortium (ExAC) 0.00022

The Genome Aggregation Database (gnomAD), exomes 0.00022

The Genome Aggregation Database (gnomAD) 0.00031

Trans-Omics for Precision Medicine (TOPMed) 0.00032

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038

Links

dbSNP: rs150373689 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
NRCAM		-	-	GRCh38 GRCh37	122	147

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
NRCAM-related disorder	Pathogenic (1)	no assertion criteria provided	Dec 28, 2021	RCV001824188.1
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Feb 27, 2023	RCV003163938.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Feb 27, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003863048.2 First in ClinVar: Apr 15, 2023 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 35108495 Comment: The c.2557C>T (p.R853C) alteration is located in exon 21 (coding exon 21) of the NRCAM gene. This alteration results from a C to T substitution … (more) The c.2557C>T (p.R853C) alteration is located in exon 21 (coding exon 21) of the NRCAM gene. This alteration results from a C to T substitution at nucleotide position 2557, causing the arginine (R) at amino acid position 853 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.023% (66/282608) total alleles studied. The highest observed frequency was 0.096% (10/10364) of Ashkenazi Jewish alleles. This variant has been reported to be compound heterozygous with c.2705A>C (p.Lys902Thr) in an individual with global developmental delay, behavioral issues, hypotonia, and ataxia (Kurolap, 2022). This amino acid position is poorly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Pathogenic (Dec 28, 2021)	no assertion criteria provided Method: research	NRCAM-related disorder Affected status: yes Allele origin: inherited	Genetics Institute, Tel Aviv Sourasky Medical Center Accession: SCV002044489.1 First in ClinVar: Feb 10, 2022 Last updated: Feb 10, 2022	Publications: PubMed (1) PubMed: 35108495

Comment:

The c.2557C>T (p.R853C) alteration is located in exon 21 (coding exon 21) of the NRCAM gene. This alteration results from a C to T substitution at nucleotide position 2557, causing the arginine (R) at amino acid position 853 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.023% (66/282608) total alleles studied. The highest observed frequency was 0.096% (10/10364) of Ashkenazi Jewish alleles. This variant has been reported to be compound heterozygous with c.2705A>C (p.Lys902Thr) in an individual with global developmental delay, behavioral issues, hypotonia, and ataxia (Kurolap, 2022). This amino acid position is poorly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.	Kurolap A	American journal of human genetics	2022	PMID: 35108495

Text-mined citations for rs150373689 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated May 12, 2024

ClinVar Genomic variation as it relates to human health

NM_001037132.4(NRCAM):c.2557C>T (p.Arg853Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs150373689 ...