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

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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:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000593111	Genetic Services Laboratory,University of Chicago	criteria provided, single submitter ACMG Guidelines, 2015	Likely benign (Mar 14, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000711944	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter LMM Criteria	Likely benign (Mar 21, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000862397	Eurofins NTD LLC (GA)	criteria provided, single submitter EGL ClinVar v180209 classification definitions	Likely benign (Jul 31, 2018)	germline	clinical testing	Citation Link,
SCV000864092	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter LabCorp Variant Classification Summary - May 2015	Uncertain significance (May 29, 2018)	germline	clinical testing	Citation Link

Summary from all submissions

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Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	3	3	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical 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

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical 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).

#	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		3	not provided	3	not provided

From Eurofins NTD LLC (GA), SCV000862397.1

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

#	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		1	not provided	not provided	not provided

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

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

#	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: Dec 24, 2022

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