VCV000134374.37 - ClinVar

NM_000043.6(FAS):c.580G>A (p.Glu194Lys)

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.

(15)

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(6); Likely benign(4)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000043.6(FAS):c.580G>A (p.Glu194Lys)

Variation ID: 134374 Accession: VCV000134374.37

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q23.31 10: 89012010 (GRCh38) [ NCBI UCSC ] 10: 90771767 (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	Jun 9, 2014	Nov 24, 2024	Jul 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000043.6:c.580G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000034.1:p.Glu194Lys	missense
NM_001320619.2:c.568+1195G>A		intron variant
NM_152871.4:c.517G>A	NP_690610.1:p.Glu173Lys	missense
NM_152872.4:c.580G>A	NP_690611.1:p.Glu194Lys	missense
NR_028033.4:n.487G>A		non-coding transcript variant
NR_028034.4:n.349G>A		non-coding transcript variant
NR_028035.4:n.412G>A		non-coding transcript variant
NR_028036.4:n.550G>A		non-coding transcript variant
NR_135314.2:n.746G>A		non-coding transcript variant
NR_135315.2:n.499G>A		non-coding transcript variant
NC_000010.11:g.89012010G>A
NC_000010.10:g.90771767G>A
NG_009089.2:g.26480G>A
LRG_134:g.26480G>A
LRG_134t1:c.580G>A

... more HGVS ... less HGVS

Protein change

E194K, E173K

Other names

p.Glu194Lys

Canonical SPDI

NC_000010.11:89012009: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.

0.00060 (A)

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

1000 Genomes Project 0.00060

1000 Genomes Project 30x 0.00062

The Genome Aggregation Database (gnomAD) 0.00138

Trans-Omics for Precision Medicine (TOPMed) 0.00142

The Genome Aggregation Database (gnomAD), exomes 0.00154

Exome Aggregation Consortium (ExAC) 0.00180

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00246

Links

ClinGen: CA159637 dbSNP: rs56006128 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.
FAS		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	409	461

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.
not specified	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Apr 23, 2024	RCV000121048.8
Autoimmune lymphoproliferative syndrome type 1	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	Jan 31, 2024	RCV000407819.25
not provided	Conflicting interpretations of pathogenicity (6)	criteria provided, conflicting classifications	Jul 1, 2024	RCV000766928.17
FAS-related disorder	Likely benign (1)	no assertion criteria provided	Jun 26, 2020	RCV003935155.2

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 (Oct 08, 2018)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321627.7 First in ClinVar: Jun 09, 2014 Last updated: Apr 17, 2019	Comment: The E194K variant in the FAS gene has been reported previously in association with autoimmune lymphoproliferative syndrome type 1A (Campagnoli et al., 2006; Rao et … (more) The E194K variant in the FAS gene has been reported previously in association with autoimmune lymphoproliferative syndrome type 1A (Campagnoli et al., 2006; Rao et al., 2009). The E194K variant is observed in 306/126,586 (0.24%) alleles from individuals of non-Finnish European background and 414/277,020 (0.15%) total alleles, including one homozygous individual, in large population cohorts (Lek et al., 2016). The E194K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Functional studies have shown that E194K decreases the function of the FAS protein (Boggio et al., 2013). We interpret E194K as a variant of uncertain significance. (less)
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Autoimmune lymphoproliferative syndrome type 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000365904.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Publications: PubMed (1) PubMed: 16537120 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Uncertain significance (Sep 06, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autoimmune lymphoproliferative syndrome type 1 Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001524336.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Uncertain significance (Mar 30, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autoimmune lymphoproliferative syndrome type 1 Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV000898684.2 First in ClinVar: Apr 25, 2019 Last updated: May 06, 2023	Comment: FAS NM_000043.5 exon7 p.Glu194Lys (c.580G>A): This variant has been reported in the literature in at least one individual with autoimmune lymphoproliferative syndrome (ALPS)(Campagnoli 2006 PMID:16537120, … (more) FAS NM_000043.5 exon7 p.Glu194Lys (c.580G>A): This variant has been reported in the literature in at least one individual with autoimmune lymphoproliferative syndrome (ALPS)(Campagnoli 2006 PMID:16537120, Boggio 2013 PMID:24043286). This variant is present in 0.2% (306/126586) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/dbsnp/rs56006128). This variant is present in ClinVar (Variation ID:134374). Evolutionary conservation and computational predictive tools for this variant are unclear. In vitro functional studies suggest that this variant will impact the protein (Boggio 2013 PMID:24043286). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. (less)
Uncertain significance (Feb 17, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autoimmune lymphoproliferative syndrome type 1 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003833948.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Likely benign (Apr 23, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005076631.1 First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024
Uncertain significance (Aug 14, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002070461.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022
Likely benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Autoimmune lymphoproliferative syndrome type 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000637309.9 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 28492532
Likely benign (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004127055.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: FAS: BP4, BS1 Number of individuals with the variant: 4
Uncertain significance (May 15, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005412175.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (8) PubMed: 16537120‚ 24043286‚ 27153395‚ 27884173‚ 31172514‚ 32441320‚ 33838017‚ 35741048 Comment: BS1, BS2, PS4_moderate Number of individuals with the variant: 2
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001928091.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Likely benign (Jun 26, 2020)	no assertion criteria provided Method: clinical testing	FAS-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004752775.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001807749.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001970375.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000085216.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation 1: Ethnicity/Population group: Whole_cohort Observation 2: Ethnicity/Population group: African Observation 3: Ethnicity/Population group: African_European Observation 4: Ethnicity/Population group: Central_Asian Observation 5: Ethnicity/Population group: East_Asian Observation 6: Ethnicity/Population group: European Observation 7: Ethnicity/Population group: Hispanic
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Comment:

The E194K variant in the FAS gene has been reported previously in association with autoimmune lymphoproliferative syndrome type 1A (Campagnoli et al., 2006; Rao et al., 2009). The E194K variant is observed in 306/126,586 (0.24%) alleles from individuals of non-Finnish European background and 414/277,020 (0.15%) total alleles, including one homozygous individual, in large population cohorts (Lek et al., 2016). The E194K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Functional studies have shown that E194K decreases the function of the FAS protein (Boggio et al., 2013). We interpret E194K as a variant of uncertain significance.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

FAS NM_000043.5 exon7 p.Glu194Lys (c.580G>A): This variant has been reported in the literature in at least one individual with autoimmune lymphoproliferative syndrome (ALPS)(Campagnoli 2006 PMID:16537120, Boggio 2013 PMID:24043286). This variant is present in 0.2% (306/126586) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/dbsnp/rs56006128). This variant is present in ClinVar (Variation ID:134374). Evolutionary conservation and computational predictive tools for this variant are unclear. In vitro functional studies suggest that this variant will impact the protein (Boggio 2013 PMID:24043286). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

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
T-Cell Defects Associated to Lack of Spike-Specific Antibodies after BNT162b2 Full Immunization Followed by a Booster Dose in Patients with Common Variable Immune Deficiencies.	Pulvirenti F	Cells	2022	PMID: 35741048
Immune cytopenias as a continuum in inborn errors of immunity: An in-depth clinical and immunological exploration.	Zama D	Immunity, inflammation and disease	2021	PMID: 33838017
Next generation sequencing analysis of consecutive Russian patients with clinical suspicion of inborn errors of immunity.	Suspitsin EN	Clinical genetics	2020	PMID: 32441320
FAS mutations are an uncommon cause of immune thrombocytopenia in children and adults without additional features of immunodeficiency.	Vandrovcova J	British journal of haematology	2019	PMID: 31172514
Revisiting the morbid genome of Mendelian disorders.	Abouelhoda M	Genome biology	2016	PMID: 27884173
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.	Maxwell KN	American journal of human genetics	2016	PMID: 27153395
Mutation of FAS, XIAP, and UNC13D genes in a patient with a complex lymphoproliferative phenotype.	Boggio E	Pediatrics	2013	PMID: 24043286
The broad spectrum of autoimmune lymphoproliferative disease: molecular bases, clinical features and long-term follow-up in 31 patients.	Campagnoli MF	Haematologica	2006	PMID: 16537120

Text-mined citations for rs56006128 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000043.6(FAS):c.580G>A (p.Glu194Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs56006128 ...