NM_000036.3(AMPD1):c.34C>T (p.Gln12Ter) AND not provided

Clinical significance:Conflicting interpretations of pathogenicity, other, Pathogenic(1);Uncertain significance(1) (Last evaluated: Nov 1, 2021)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000487355.7

Allele description [Variation Report for NM_000036.3(AMPD1):c.34C>T (p.Gln12Ter)]

NM_000036.3(AMPD1):c.34C>T (p.Gln12Ter)

Gene:
AMPD1:adenosine monophosphate deaminase 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1p13.2
Genomic location:
Preferred name:
NM_000036.3(AMPD1):c.34C>T (p.Gln12Ter)
HGVS:
  • NC_000001.11:g.114693436G>A
  • NG_008012.1:g.7120C>T
  • NM_000036.2:c.133C>T
  • NM_000036.3:c.34C>TMANE SELECT
  • NM_001172626.2:c.22+2014C>T
  • NP_000027.2:p.Gln45Ter
  • NP_000027.3:p.Gln12Ter
  • NC_000001.10:g.115236057G>A
  • NP_000027.2:p.Gln45*
Note:
NCBI staff reviewed the sequence information reported in PubMed 1631143 to determine the location of this allele on current reference sequence.
Protein change:
Q45*
Links:
OMIM: 102770.0001; dbSNP: rs17602729
NCBI 1000 Genomes Browser:
rs17602729
Molecular consequence:
  • NM_001172626.2:c.22+2014C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000036.2:c.133C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_000036.3:c.34C>T - nonsense - [Sequence Ontology: SO:0001587]
Observations:
199

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000568077GeneDxcriteria provided, single submitter
Uncertain significance
(Nov 1, 2021)
germlineclinical testing

Citation Link,

SCV000802453Mayo Clinic Laboratories, Mayo Clinicno assertion criteria providedPathogenic
(Feb 19, 2016)
unknownclinical testing

SCV000854814EGL Genetic Diagnostics, Eurofins Clinical Diagnosticscriteria provided, single submitter
other
(Feb 7, 2018)
germlineclinical testing

Citation Link,

SCV001446914Institute of Medical Genetics and Applied Genomics, University Hospital Tübingencriteria provided, single submitter
Pathogenic
(Oct 23, 2020)
germlineclinical testing

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

SCV001551404Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria providedUncertain significanceunknownclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot provided1not providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknown199not providednot providednot providednot providedclinical testing
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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 GeneDx, SCV000568077.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21686757, 29143670, 29095874, 25525159, 1631143, 8335021, 32596782, 32483371, 33250842, 15239633, 15378456, 14499869, 23300193, 16021918, 18855224, 12117480, 21343608, 10918252, 29422864, 29749052, 30429902, 28751290, 30837873, 31867206, 32379996, 24508110)

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

From Mayo Clinic Laboratories, Mayo Clinic, SCV000802453.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From EGL Genetic Diagnostics, Eurofins Clinical Diagnostics, SCV000854814.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided199not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided199not providednot providednot provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001446914.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot providednot providednot providednot providednot provided

From Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001551404.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The AMPD1 p.Gln45* variant has been reported in multiple homozygous individuals with AMPD deficiency but has also been reported in multiple healthy controls, including athletes (Morisaki_1992_PMID:1631143; Gronek_2018_PMID:30429902; Nikolova_2015_PMID:26380113; Gineviciene_2014_PMID:24885427). The variant was identified in dbSNP (ID: rs17602729) and ClinVar (classified as uncertain significance by GeneDx and Invitae, and as pathogenic by Mayo Clinic). The variant was identified in control databases in 24609 of 282334 chromosomes (1470 homozygous) at a frequency of 0.08716 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 16882 of 128928 chromosomes (freq: 0.1309), European (Finnish) in 2903 of 25048 chromosomes (freq: 0.1159), Other in 682 of 7188 chromosomes (freq: 0.09488), Ashkenazi Jewish in 790 of 10360 chromosomes (freq: 0.07625), Latino in 1757 of 35356 chromosomes (freq: 0.04969), South Asian in 1078 of 30602 chromosomes (freq: 0.03523), African in 516 of 24900 chromosomes (freq: 0.02072), and East Asian in 1 of 19952 chromosomes (freq: 0.00005). The c.133C>T variant leads to a premature stop codon at position 45, which is predicted to lead to a truncated or absent protein and loss of function. It is unclear how loss of function variants of the AMPD1 gene contribute to autosomal recessive AMPD deficiency; further, many individuals with AMPD deficiency are asymptomatic. The p.Gln45* variant occurs in the last base of the exon; this position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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

Last Updated: Nov 27, 2021

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