NM_001378454.1(ALMS1):c.2221dup (p.Thr741fs) AND Alstrom syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jun 9, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000667941.4

Allele description [Variation Report for NM_001378454.1(ALMS1):c.2221dup (p.Thr741fs)]

NM_001378454.1(ALMS1):c.2221dup (p.Thr741fs)

Gene:

ALMS1:ALMS1 centrosome and basal body associated protein [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

2p13.1

Genomic location:

Preferred name:

NM_001378454.1(ALMS1):c.2221dup (p.Thr741fs)

HGVS:

NC_000002.12:g.73448748dup
NG_011690.1:g.67996dup
NM_001378454.1:c.2221dupMANE SELECT
NM_015120.4:c.2224dup
NP_001365383.1:p.Thr741fs
NP_055935.4:p.Thr742fs
LRG_741t1:c.2224dup
LRG_741:g.67996dup
LRG_741p1:p.Thr742fs
NC_000002.11:g.73675874_73675875insA
NC_000002.11:g.73675875dup
NM_015120.4:c.2224dupA

Protein change:

T741fs

Links:

dbSNP: rs769291842

NCBI 1000 Genomes Browser:

rs769291842

Molecular consequence:

NM_001378454.1:c.2221dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_015120.4:c.2224dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Alstrom syndrome (ALMS)
Synonyms:: Alstrom's syndrome
Identifiers:: MONDO: MONDO:0008763; MedGen: C0268425; Orphanet: 64; OMIM: 203800

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000792470	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Jun 26, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV003497565	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 9, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28432734, 17594715, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000792470

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Likely pathogenic
(Jun 26, 2017)

unknown

clinical testing

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

Citation Link,

SCV003497565

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 9, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Diffuse left ventricular interstitial fibrosis is associated with sub-clinical myocardial dysfunction in Alström Syndrome: an observational study.

Edwards NC, Moody WE, Yuan M, Warfield AT, Cramb R, Paisey RB, Geberhiwot T, Steeds RP.

Orphanet J Rare Dis. 2015 Jun 24;10:83. doi: 10.1186/s13023-015-0292-z.

PubMed [citation]

PMID:: 26104972
PMCID:: PMC4483224

Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia.

Astuti D, Sabir A, Fulton P, Zatyka M, Williams D, Hardy C, Milan G, Favaretto F, Yu-Wai-Man P, Rohayem J, López de Heredia M, Hershey T, Tranebjaerg L, Chen JH, Chaussenot A, Nunes V, Marshall B, McAfferty S, Tillmann V, Maffei P, Paquis-Flucklinger V, Geberhiwot T, et al.

Hum Mutat. 2017 Jul;38(7):764-777. doi: 10.1002/humu.23233. Epub 2017 Jun 1.

PubMed [citation]

PMID:: 28432734
PMCID:: PMC5535005

See all PubMed Citations (4)

Details of each submission

From Counsyl, SCV000792470.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003497565.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 552645). This premature translational stop signal has been observed in individual(s) with ALMS1-related conditions (PMID: 28432734). This variant is present in population databases (rs769291842, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Thr742Asnfs*2) in the ALMS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALMS1 are known to be pathogenic (PMID: 17594715).

#	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: Sep 29, 2024

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