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NM_020458.4(TTC7A):c.1817A>G (p.Lys606Arg) AND not specified

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Dec 13, 2020
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:
RCV001280647.2

Allele description [Variation Report for NM_020458.4(TTC7A):c.1817A>G (p.Lys606Arg)]

NM_020458.4(TTC7A):c.1817A>G (p.Lys606Arg)

Gene:
TTC7A:tetratricopeptide repeat domain 7A [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2p21
Genomic location:
Preferred name:
NM_020458.4(TTC7A):c.1817A>G (p.Lys606Arg)
HGVS:
  • NC_000002.12:g.47046329A>G
  • NG_034143.2:g.135201A>G
  • NM_001288951.2:c.1817A>G
  • NM_001288953.2:c.1715A>G
  • NM_001288955.2:c.755A>G
  • NM_020458.4:c.1817A>GMANE SELECT
  • NP_001275880.1:p.Lys606Arg
  • NP_001275882.1:p.Lys572Arg
  • NP_001275884.1:p.Lys252Arg
  • NP_065191.2:p.Lys606Arg
  • LRG_1323t1:c.1817A>G
  • LRG_1323:g.135201A>G
  • LRG_1323p1:p.Lys606Arg
  • NC_000002.11:g.47273468A>G
  • NG_034143.1:g.135201A>G
  • NM_020458.3:c.1817A>G
Protein change:
K252R; LYS606ARG
Links:
OMIM: 609332.0008; dbSNP: rs139010200
NCBI 1000 Genomes Browser:
rs139010200
Molecular consequence:
  • NM_001288951.2:c.1817A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001288953.2:c.1715A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001288955.2:c.755A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_020458.4:c.1817A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001467888Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Uncertain significance
(Dec 13, 2020)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Integrated analysis of germline and somatic variants in ovarian cancer.

Kanchi KL, Johnson KJ, Lu C, McLellan MD, Leiserson MD, Wendl MC, Zhang Q, Koboldt DC, Xie M, Kandoth C, McMichael JF, Wyczalkowski MA, Larson DE, Schmidt HK, Miller CA, Fulton RS, Spellman PT, Mardis ER, Druley TE, Graubert TA, Goodfellow PJ, Raphael BJ, et al.

Nat Commun. 2014;5:3156. doi: 10.1038/ncomms4156.

PubMed [citation]
PMID:
24448499
PMCID:
PMC4025965

TTC7A Variants Previously Described to Cause Enteropathy Are Observed on a Single Haplotype and Appear Non-pathogenic in Pediatric Inflammatory Bowel Disease Patients.

Ashton JJ, Mossotto E, Beattie RM, Ennis S.

J Clin Immunol. 2020 Jan;40(1):245-247. doi: 10.1007/s10875-019-00726-0. Epub 2019 Dec 9. No abstract available.

PubMed [citation]
PMID:
31814065
See all PubMed Citations (9)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001467888.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

Variant summary: TTC7A c.1817A>G (p.Lys606Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 251304 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 6-fold the estimated maximal expected allele frequency for a pathogenic variant in TTC7A causing Severe Combined Immunodeficiency Syndrome phenotype (0.00035), suggesting that the variant is benign. c.1817A>G has been reported in the literature in cis with c.2014T>C, p.Ser672Pro in at least one individual affected with Combined Immunodeficiency with Multiple Intestinal Atresias (CID-MIA), who had a likely pathogenic variant (c.1000DelAAGT) in compound heterozygosity (e.g. Chen_2013). The variant has also been detected in several patients with early-onset inflammatory bowel disease (EOIBD) or inflammatory bowel disease (IBD), often occurring along with c.2014T>C, p.Ser672Pro (e.g. Kammermeier_2016, Petersen_2017, Ashton, 2020). In some cases, the variants were indicated to have been inherited as a complex allele, while in others, the phase was not reported. However, these two variants were also reported in trans in at least one individual affected by a mild form of Combined Variable Immunodeficiency Syndrome (CVID), suggesting that the variants could possibly be associated with a mild form of disease when found on separate alleles (e.g. Lawless_2017). The c.1817A>G and c.2014T>C variants were also reported in compound heterozygosity in an individual evaluated for IPEX (Immune Dysregulation, Polyendocrinopathy, Ebteropathy, X-Linked) Syndrome (e.g. Gambineri_2018). These findings do not provide unequivocal evidence for association of the variant with Severe Combined Immunodeficiency Syndrome. To the best of our knowledge, no experimental studies evaluating an impact on protein function have been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory cited the variant as likely benign, and one laboratory cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 26, 2024