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NM_001378454.1(ALMS1):c.4988C>T (p.Thr1663Ile) AND not specified

Clinical significance:Conflicting interpretations of pathogenicity, Uncertain significance(1); Likely benign(3) (Last evaluated: Jul 31, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000433447.16

Allele description [Variation Report for NM_001378454.1(ALMS1):c.4988C>T (p.Thr1663Ile)]

NM_001378454.1(ALMS1):c.4988C>T (p.Thr1663Ile)

Gene:
ALMS1:ALMS1 centrosome and basal body associated protein [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2p13.1
Genomic location:
Preferred name:
NM_001378454.1(ALMS1):c.4988C>T (p.Thr1663Ile)
HGVS:
  • NC_000002.12:g.73451515C>T
  • NG_011690.1:g.70763C>T
  • NM_001378454.1:c.4988C>TMANE SELECT
  • NM_015120.4:c.4991C>T
  • NP_001365383.1:p.Thr1663Ile
  • NP_055935.4:p.Thr1664Ile
  • LRG_741t1:c.4991C>T
  • LRG_741:g.70763C>T
  • LRG_741p1:p.Thr1664Ile
  • NC_000002.11:g.73678642C>T
  • p.Thr1662Ile
Protein change:
T1663I
Links:
dbSNP: rs188807564
NCBI 1000 Genomes Browser:
rs188807564
Molecular consequence:
  • NM_001378454.1:c.4988C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_015120.4:c.4991C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
3

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
SCV000593111Genetic Services Laboratory,University of Chicagocriteria provided, single submitter
Likely benign
(Mar 14, 2016)
germlineclinical testing

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

SCV000711944Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicinecriteria provided, single submitter
Likely benign
(Mar 21, 2016)
germlineclinical testing

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

SCV000862397Eurofins NTD LLC (GA)criteria provided, single submitter
Likely benign
(Jul 31, 2018)
germlineclinical testing

Citation Link,

SCV000864092Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Uncertain significance
(May 29, 2018)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenonot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided33not providednot providednot providedclinical testing
not providedgermlineunknown1not 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

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]
PMID:
24033266
PMCID:
PMC3995020

Details of each submission

From Genetic Services Laboratory,University of Chicago, SCV000593111.1

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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000711944.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providednot providedclinical testing PubMed (1)

Description

p.Thr1662Ile in exon 8 of ALMS1: This variant is not expected to have clinical s ignificance because it has been identified in 0.86% (83/9656) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs188807564).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided3not provided3not provided

From Eurofins NTD LLC (GA), SCV000862397.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000864092.2

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

Description

Variant summary: ALMS1 c.4985C>T (p.Thr1662Ile, alternative name c.4991C>T) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00073 in 276668 control chromosomes, predominantly at a frequency of 0.008 within the African subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 3.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in ALMS1 causing Cardiomyopathy phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. The variant, c.4985C>T, has not been reported in the literature in individuals affected with Cardiomyopathy. These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign x4, VUS x1). 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: Dec 24, 2022

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