NM_001083116.3(PRF1):c.272C>T (p.Ala91Val) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity; risk factor (4 submissions)
Last evaluated:: Sep 12, 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:: RCV000224458.9

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_001083116.3: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]

Observations:

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000280651	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 26, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000617803	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	risk factor (Mar 18, 2021)	germline	clinical testing	Citation Link,
SCV001550951	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Likely benign	unknown	clinical testing
SCV005411044	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 12, 2024)	germline	clinical testing	PubMed (27) [See all records that cite these PMIDs] 12229880, 15741215, 16611257, 21881043, 22437823, 22970278, 23073290, 23592409, 24916509, 25776844, 25937001, 26597256, 27872624, 28863861, 31932842, 32342501, 32542393, 32853466, 33566725, 34339548, 36706356, 37390248, 37678575, 37992218, 38383762, 38474010, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	25	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations.

Clementi R, Emmi L, Maccario R, Liotta F, Moretta L, Danesino C, Aricó M.

Blood. 2002 Sep 15;100(6):2266-7. No abstract available.

PubMed [citation]

PMID:: 12229880

A single amino acid change, A91V, leads to conformational changes that can impair processing to the active form of perforin.

Trambas C, Gallo F, Pende D, Marcenaro S, Moretta L, De Fusco C, Santoro A, Notarangelo L, Arico M, Griffiths GM.

Blood. 2005 Aug 1;106(3):932-7. Epub 2005 Mar 1.

PubMed [citation]

PMID:: 15741215

See all PubMed Citations (27)

Details of each submission

From Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, SCV000280651.2

#	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	not provided	not provided	not provided	not provided		not provided	0.042603	not provided	not provided

From GeneDx, SCV000617803.1

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

Description

Identified in individuals with familial hemophagocytic lymphohistiocytosis and acute lymophoblastic leukemia; however, the A91V variant has also been identified in both unaffected relatives and unaffected controls (Zur Stadt et al., 2004; Santoro et al., 2005; An et al., 2013); Functional studies suggest that the A91V variant results in decreased levels of perforin expression, with partial loss of protein function and stability (Voskoboinik et al., 2005; House et al., 2015); This variant is associated with the following publications: (PMID: 33256384, 32150605, 32198610, 32342501, 32542393, 32300447, 31932842, 30957677, 29263817, 30343897, 30287596, 14757862, 24916509, 27622035, 28863861, 27153395, 27872624, 15342365, 23592409, 26597256, 24632576, 22970278, 25937001, 25121636, 24309606, 22437823, 16611257, 25776844, 23073290, 25354579, 18496551, 17311987, 17475905, 15741215, 12229880, 21881043, 15755897, 15921391)

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

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001550951.1

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

Description

The PRF1 p.Ala91Val variant was identified in the literature, however the role of its pathogenicity has been debated. The variant was identified in 15 of 320 proband chromosomes (frequency: 0.053) from individuals or families with haemophagocytic lymphohistiocytosis (HLH), acquired aplastic anemia, and Dianzani Autoimmune Lymphoproliferative Disease (Molleran_2004_PMID: 14757862, Solomou_2007_PMID: 17311987 & Clementi_2006_PMID: 16720836). The variant has also been reported in control population in multiple studies at frequencies of 0.046, 0.010, 0.0174 and 0.087 (Lek_2016_PMID: 27535533, Zur Stadt_2004_PMID: 15342365; Solomou_2007_PMID: 17311987 & Clementi_2006_PMID: 16720836). The variant was identified in dbSNP (ID: rs35947132) as â€šÃ„ÃºWith Pathogenic alleleâ€šÃ„Ã¹. In ClinVar, there are conflicting interpretations of pathogenicity from six submitters: 1x pathogenic (Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics), 2x likely benign (Illumina Clinical Services Laboratory and Invitae), 1x benign (Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine), and 2x uncertain significance (GeneDx and OMIM). The associated conditions are Hemophagocytic lymphohistiocytosis, familial, 2 and Familial hemophagocytic lymphohistiocytosis. The variant was also identified in LOVD 3.0 but was not found in Cosmic. The variant was identified in control databases in 8191 of 280896 chromosomes (171 homozygous) at a frequency of 0.02916 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 5912 of 128018 chromosomes (freq: 0.04618), Other in 252 of 7176 chromosomes (freq: 0.03512), Ashkenazi Jewish in 273 of 10298 chromosomes (freq: 0.02651), European (Finnish) in 655 of 24848 chromosomes (freq: 0.02636), Latino in 811 of 35320 chromosomes (freq: 0.02296), African in 153 of 24738 chromosomes (freq: 0.006185), South Asian in 132 of 30580 chromosomes (freq: 0.004317), and East Asian in 3 of 19918 chromosomes (freq: 0.000151). Perforin plays a key role in the cytotoxicity of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). A functional study of the p.A91V variant showed that the variant resulted in impaired cleavage of perforin to its active form, resulting in loss of CTL and NK-cell cytotoxicity against targets (Trambas_2005_PMID: 15741215). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. The p.Ala91 residue is not highly conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, and MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this varaint. This variant is classified as a variant of likely benign.

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

From Mayo Clinic Laboratories, Mayo Clinic, SCV005411044.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	25	not provided	not provided	clinical testing	PubMed (27)

Description

BS1, BS2, PM3, PS3

#	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		25	not provided	not provided	not provided

Last Updated: Nov 30, 2024

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