VCV001739214.7 - ClinVar

NM_001042492.3(NF1):c.4331A>C (p.Lys1444Thr)

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.

(3)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001042492.3(NF1):c.4331A>C (p.Lys1444Thr)

Variation ID: 1739214 Accession: VCV001739214.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q11.2 17: 31258501 (GRCh38) [ NCBI UCSC ] 17: 29585519 (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	Nov 29, 2022	Oct 8, 2024	May 18, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001042492.3:c.4331A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001035957.1:p.Lys1444Thr	missense
NM_000267.3:c.4268A>C	NP_000258.1:p.Lys1423Thr	missense
NC_000017.11:g.31258501A>C
NC_000017.10:g.29585519A>C
NG_009018.1:g.168525A>C
LRG_214:g.168525A>C
LRG_214t1:c.4268A>C	LRG_214p1:p.Lys1423Thr
LRG_214t2:c.4331A>C	LRG_214p2:p.Lys1444Thr

... more HGVS ... less HGVS

Protein change

K1423T, K1444T

Other names

Canonical SPDI

NC_000017.11:31258500:A:C

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.

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

Links

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.
NF1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh38 GRCh37	14135	14574

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.
Cardiovascular phenotype Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Dec 13, 2021	RCV002329989.2
Neurofibromatosis, type 1	Pathogenic (1)	criteria provided, single submitter	-	RCV003108023.5
not provided	Pathogenic (1)	criteria provided, single submitter	May 18, 2023	RCV004721048.1

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.
Pathogenic (Dec 13, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Hereditary cancer-predisposing syndrome Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002629955.2 First in ClinVar: Nov 29, 2022 Last updated: Jun 09, 2024	Comment: The p.K1423T variant (also known as c.4268A>C), located in coding exon 31 of the NF1 gene, results from an A to C substitution at nucleotide … (more) The p.K1423T variant (also known as c.4268A>C), located in coding exon 31 of the NF1 gene, results from an A to C substitution at nucleotide position 4268. The lysine at codon 1423 is replaced by threonine, an amino acid with similar properties. This alteration has been identified in multiple individuals with a clinical diagnosis of neurofibromatosis type 1 (NF1) (Koczkowska M et al. Hum Mutat, 2020 01;41:299-315). Two other alterations at the same codon, p.K1423Q (c.4267A>C) and p.K1423E (c.4267A>G), have also been been identified in multiple individuals with a clinical diagnosis of NF1 (Li Y, et al. Cell 1992; 69(2):275-81; Wang Q, et al. Hum. Genet. 2003;112(2):117-23; Pros E, et al. Hum. Mutat. 2008;29(9):E173-93; Upadhyaya M, et al. Hum. Mutat. 2008; 29(8):E103-11; Thomas L, et al. Hum. Mutat. 2012;33(12):1687-96; Cassiman C et al. Clin. Genet., 2017 Apr;91:529-535; Cannon A et al. Orphanet J Rare Dis, 2018 Feb;13:31; Koczkowska M et al. Hum Mutat, 2020 01;41:299-315). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurofibromatosis, type 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Suma Genomics Accession: SCV003762220.2 First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023
Pathogenic (May 18, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005328150.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22807134, 25486365, 31595648) (less)

Comment:

The p.K1423T variant (also known as c.4268A>C), located in coding exon 31 of the NF1 gene, results from an A to C substitution at nucleotide position 4268. The lysine at codon 1423 is replaced by threonine, an amino acid with similar properties. This alteration has been identified in multiple individuals with a clinical diagnosis of neurofibromatosis type 1 (NF1) (Koczkowska M et al. Hum Mutat, 2020 01;41:299-315). Two other alterations at the same codon, p.K1423Q (c.4267A>C) and p.K1423E (c.4267A>G), have also been been identified in multiple individuals with a clinical diagnosis of NF1 (Li Y, et al. Cell 1992; 69(2):275-81; Wang Q, et al. Hum. Genet. 2003;112(2):117-23; Pros E, et al. Hum. Mutat. 2008;29(9):E173-93; Upadhyaya M, et al. Hum. Mutat. 2008; 29(8):E103-11; Thomas L, et al. Hum. Mutat. 2012;33(12):1687-96; Cassiman C et al. Clin. Genet., 2017 Apr;91:529-535; Cannon A et al. Orphanet J Rare Dis, 2018 Feb;13:31; Koczkowska M et al. Hum Mutat, 2020 01;41:299-315). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22807134, 25486365, 31595648)

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_001042492.3(NF1):c.4331A>C (p.Lys1444Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...