NM_001083116.3(PRF1):c.272C>T (p.Ala91Val) AND Familial hemophagocytic lymphohistiocytosis 2

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Mar 25, 2024
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:: RCV000547554.19

Allele description [Variation Report for NM_001083116.3(PRF1):c.272C>T (p.Ala91Val)]

NM_001083116.3(PRF1):c.272C>T (p.Ala91Val)

Gene:

PRF1:perforin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q22.1

Genomic location:

Preferred name:

NM_001083116.3(PRF1):c.272C>T (p.Ala91Val)

HGVS:

NC_000010.11:g.70600631G>A
NG_009615.1:g.7145C>T
NM_001083116.3:c.272C>TMANE SELECT
NM_005041.5:c.272C>T
NM_005041.6:c.272C>T
NP_001076585.1:p.Ala91Val
NP_005032.2:p.Ala91Val
LRG_94t1:c.272C>T
LRG_94:g.7145C>T
NC_000010.10:g.72360387G>A
NM_001083116.1:c.272C>T
NM_005041.4:c.272C>T
P14222:p.Ala91Val

Protein change:

A91V; ALA91VAL

Links:

UniProtKB: P14222#VAR_050482; OMIM: 170280.0011; dbSNP: rs35947132

NCBI 1000 Genomes Browser:

rs35947132

Molecular consequence:

NM_001083116.3:c.272C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005041.6:c.272C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hemophagocytic lymphohistiocytosis 2 (FHL2)
Identifiers:: MONDO: MONDO:0011337; MedGen: C1863727; Orphanet: 540; OMIM: 603553

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Lactiplantibacillus plantarum strain 3.2.8 phosphoglucomutase (pgm) gene, partial cds
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000363438	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Benign (Mar 6, 2018)	germline	clinical testing	Citation Link,
SCV000644881	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Feb 1, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001138067	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Likely benign (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001976569	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 32356861, 32150605, 19487666
SCV004805429	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 25, 2024)	germline	research	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only, research
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Functional and genetic testing in adults with HLH reveals an inflammatory profile rather than a cytotoxicity defect.

Carvelli J, Piperoglou C, Farnarier C, Vely F, Mazodier K, Audonnet S, Nitschke P, Bole-Feysot C, Boucekine M, Cambon A, Hamidou M, Harle JR, de Saint Basile G, Kaplanski G.

Blood. 2020 Jul 30;136(5):542-552. doi: 10.1182/blood.2019003664.

PubMed [citation]

PMID:: 32356861
PMCID:: PMC7530375

See all PubMed Citations (5)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000363438.3

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

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

From Invitae, SCV000644881.6

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV001138067.1

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

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

From GeneReviews, SCV001976569.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

Description

Variant assoc w/late-onset (adult) fHLH [Carvelli et al 2020, Miller et al 2020]. Common variant in population studies of healthy persons; functional effects were studied [Chia et al 2009].

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

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004805429.2

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

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

Last Updated: May 19, 2024

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