NM_005262.3(GFER):c.199del (p.Arg67fs) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 11, 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:: RCV000200750.3

Allele description [Variation Report for NM_005262.3(GFER):c.199del (p.Arg67fs)]

NM_005262.3(GFER):c.199del (p.Arg67fs)

Genes:

LOC130058203:ATAC-STARR-seq lymphoblastoid silent region 7014 [Gene]
GFER:growth factor, augmenter of liver regeneration [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_005262.3(GFER):c.199del (p.Arg67fs)

HGVS:

NC_000016.10:g.1984417del
NG_016288.1:g.5269del
NM_005262.3:c.199delMANE SELECT
NP_005253.3:p.Arg67fs
NC_000016.9:g.2034416del
NC_000016.9:g.2034418del
NM_005262.2:c.199delC
p.R67fsX83

Protein change:

R67fs

Links:

dbSNP: rs863224028

NCBI 1000 Genomes Browser:

rs863224028

Molecular consequence:

NM_005262.3:c.199del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000251540	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely pathogenic (Sep 14, 2018)	germline	clinical testing	Citation Link,
SCV004665080	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 11, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34732400, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000251540

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely pathogenic
(Sep 14, 2018)

germline

clinical testing

Citation Link,

SCV004665080

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 11, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study.

Schon KR, Horvath R, Wei W, Calabrese C, Tucci A, Ibañez K, Ratnaike T, Pitceathly RDS, Bugiardini E, Quinlivan R, Hanna MG, Clement E, Ashton E, Sayer JA, Brennan P, Josifova D, Izatt L, Fratter C, Nesbitt V, Barrett T, McMullen DJ, Smith A, et al.

BMJ. 2021 Nov 3;375:e066288. doi: 10.1136/bmj-2021-066288.

PubMed [citation]

PMID:: 34732400
PMCID:: PMC8565085

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

Details of each submission

From GeneDx, SCV000251540.4

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

Description

c.199delC:p.Arg67GlyfsX83 (R67GfsX83) in exon 1 of the GFER gene (NM_005262.2). The normal sequence with the base that is deleted in braces is: CTCC{C}GGAG. The c.199delC variant in the GFER gene causes a frameshift starting with codon Arginine 67, changes this amino acid to a Glycine residue and creates a premature Stop codon at position 83 of the new reading frame, denoted p.Arg67GlyfsX83. It has not been published as pathogenic, nor has it been reported as a benign polymorphism to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay; however, to date no frameshift variants have been reported in the GFER gene. The c.199delC variant is a good candidate for a pathogenic variant, but the possibility it may be a rare benign variant cannot be excluded.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004665080.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change creates a premature translational stop signal (p.Arg67Glyfs*83) in the GFER gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 139 amino acid(s) of the GFER protein. This variant is present in population databases (rs747241374, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with clinical features of GFER-related condition (PMID: 34732400). ClinVar contains an entry for this variant (Variation ID: 214476). 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.

#	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: Sep 29, 2024

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