NM_001031710.3(KLHL7):c.976C>T (p.Arg326Ter) AND PERCHING syndrome

Germline classification:: Pathogenic (2 submissions)
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000991232.5

Allele description [Variation Report for NM_001031710.3(KLHL7):c.976C>T (p.Arg326Ter)]

NM_001031710.3(KLHL7):c.976C>T (p.Arg326Ter)

Gene:

KLHL7:kelch like family member 7 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p15.3

Genomic location:

Preferred name:

NM_001031710.3(KLHL7):c.976C>T (p.Arg326Ter)

HGVS:

NC_000007.14:g.23165737C>T
NG_016983.2:g.65004C>T
NM_001031710.3:c.976C>TMANE SELECT
NM_018846.5:c.832C>T
NP_001026880.2:p.Arg326Ter
NP_061334.4:p.Arg278Ter
NC_000007.13:g.23205356C>T
NG_016983.1:g.65004C>T
NM_001031710.2:c.976C>T
NR_033328.2:n.1349C>T
p.Arg326*

Protein change:

R278*; ARG326TER

Links:

OMIM: 611119.0011; dbSNP: rs77078070

NCBI 1000 Genomes Browser:

rs77078070

Molecular consequence:

NR_033328.2:n.1349C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001031710.3:c.976C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_018846.5:c.832C>T - nonsense - [Sequence Ontology: SO:0001587]

Functional consequence:

Unknown function

Condition(s)

Name:: PERCHING syndrome (PERCHING)
Synonyms:: Cold-induced sweating syndrome 3
Identifiers:: MONDO: MONDO:0014890; MedGen: C4310742; Orphanet: 157820; OMIM: 617055

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001142628	OMIM	no assertion criteria provided	Pathogenic (Jan 9, 2020)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002820224	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001142628

OMIM

no assertion criteria provided

Pathogenic
(Jan 9, 2020)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV002820224

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Two siblings with a novel nonsense variant provide further delineation of the spectrum of recessive KLHL7 diseases.

Jeffries L, Olivieri JE, Ji W, Spencer-Manzon M, Bale A, Konstantino M, Lakhani SA.

Eur J Med Genet. 2019 Sep;62(9):103551. doi: 10.1016/j.ejmg.2018.10.003. Epub 2018 Oct 6.

PubMed [citation]

PMID:: 30300710

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV001142628.1

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

Description

In 2 sibs, born of Guatemalan parents with possible remote consanguinity, with PERCHING syndrome (PERCHING; 617055), Jeffries et al. (2019) identified a homozygous c.976C-T transition (c.976C-T, NM_001031710.2) in the KLHL7 gene, resulting in an arg326-to-ter (R326X) substitution in the beginning of the Kelch-repeat domain for substrate binding. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found once in the heterozygous state in the gnomAD database (1 in 82,000). Functional studies of the variant and studies of patient cells were not performed, but variant was predicted to result in nonsense-mediated mRNA decay and a loss of function. The authors noted that c.832C-T;p.R278X is an equivalent variant on a different KLHL7 transcript (NM_018846.4).

#	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	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV002820224.1

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

Description

The stop gained p.R326* in KLHL7 (NM_001031710.3) has been previously reported in individuals affected with Perching Syndrome (Jeffries et al, 2019). This variant is predicted to cause loss of normal protein function through protein truncation. The p.R326* variant is a loss of function variant in the gene KLHL7, which is intolerant of Loss of Function variants. The nucleotide change in KLHL7 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

#	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

Last Updated: Jun 23, 2024

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