VCV000457891.12 - ClinVar

NM_000268.4(NF2):c.1271G>T (p.Arg424Leu)

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.

(4)

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.

Conflicting classifications of pathogenicity
Uncertain significance(2); Benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000268.4(NF2):c.1271G>T (p.Arg424Leu)

Variation ID: 457891 Accession: VCV000457891.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q12.2 22: 29673417 (GRCh38) [ NCBI UCSC ] 22: 30069406 (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	May 26, 2018	May 1, 2024	Nov 24, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000268.4:c.1271G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000259.1:p.Arg424Leu	missense
NM_016418.5:c.1271G>T	NP_057502.2:p.Arg424Leu	missense
NM_181825.3:c.1271G>T	NP_861546.1:p.Arg424Leu	missense
NM_181828.3:c.1145G>T	NP_861966.1:p.Arg382Leu	missense
NM_181829.3:c.1148G>T	NP_861967.1:p.Arg383Leu	missense
NM_181830.3:c.1022G>T	NP_861968.1:p.Arg341Leu	missense
NM_181831.3:c.1022G>T	NP_861969.1:p.Arg341Leu	missense
NM_181832.3:c.1271G>T	NP_861970.1:p.Arg424Leu	missense
NM_181833.3:c.448-21335G>T		intron variant
NR_156186.2:n.1753G>T		non-coding transcript variant
NC_000022.11:g.29673417G>T
NC_000022.10:g.30069406G>T
NG_009057.1:g.74862G>T
LRG_511:g.74862G>T
LRG_511t1:c.1271G>T	LRG_511p1:p.Arg424Leu
LRG_511t2:c.1271G>T	LRG_511p2:p.Arg424Leu

... more HGVS ... less HGVS

Protein change

R424L, R382L, R341L, R383L

Other names

Canonical SPDI

NC_000022.11:29673416:G:T

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

ClinGen: CA029388 dbSNP: rs751182657 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.
NF2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	-	-

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.
Neurofibromatosis, type 2	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Nov 24, 2023	RCV000558170.11
Hereditary cancer-predisposing syndrome	Benign (1)	criteria provided, single submitter	Jan 24, 2022	RCV002377021.2

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 (Nov 24, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Neurofibromatosis, type 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000628844.7 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Comment: This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 424 of the NF2 protein (p.Arg424Leu). … (more) This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 424 of the NF2 protein (p.Arg424Leu). This variant is present in population databases (rs751182657, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with NF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 457891). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NF2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurofibromatosis, type 2 Affected status: unknown Allele origin: germline	Molecular Genetics, Royal Melbourne Hospital Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002503649.2 First in ClinVar: Apr 28, 2022 Last updated: Apr 15, 2024	Comment: This sequence change in NF2 is predicted to replace arginine with leucine at codon 424, p.(Arg424Leu). The arginine residue is highly conserved (99/99 vertebrates, UCSC), … (more) This sequence change in NF2 is predicted to replace arginine with leucine at codon 424, p.(Arg424Leu). The arginine residue is highly conserved (99/99 vertebrates, UCSC), and is located in a coiled-coiled domain. There is a moderate physicochemical difference between arginine and leucine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.009% (3/34,206 alleles) in the Latino/Admixed American population. To our knowledge, this variant has not been reported in the relevant scientific literature. Computational evidence is uninformative for the missense substitution (REVEL = 0.322). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: none. (less)
Benign (Jan 24, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002687205.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
not provided (-)	no classification provided Method: phenotyping only	Neurofibromatosis, type 2 Affected status: unknown Allele origin: unknown	GenomeConnect - Invitae Patient Insights Network Accession: SCV001749323.1 First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021	Comment: Variant interpreted as Uncertain significance and reported on 09-29-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more) Variant interpreted as Uncertain significance and reported on 09-29-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less) Clinical Features: Breast carcinoma (present) Indication for testing: Diagnostic Age: 60-69 years Sex: female Testing laboratory: Invitae Date variant was reported to submitter: 2017-09-29 Testing laboratory interpretation: Uncertain significance

Comment:

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 424 of the NF2 protein (p.Arg424Leu). This variant is present in population databases (rs751182657, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with NF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 457891). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NF2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

This sequence change in NF2 is predicted to replace arginine with leucine at codon 424, p.(Arg424Leu). The arginine residue is highly conserved (99/99 vertebrates, UCSC), and is located in a coiled-coiled domain. There is a moderate physicochemical difference between arginine and leucine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.009% (3/34,206 alleles) in the Latino/Admixed American population. To our knowledge, this variant has not been reported in the relevant scientific literature. Computational evidence is uninformative for the missense substitution (REVEL = 0.322). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: none.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

Variant interpreted as Uncertain significance and reported on 09-29-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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 rs751182657 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000268.4(NF2):c.1271G>T (p.Arg424Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs751182657 ...