NM_001080453.3(INTS1):c.229C>T (p.Arg77Cys) AND Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: May 7, 2021
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:: RCV000850269.3

Allele description [Variation Report for NM_001080453.3(INTS1):c.229C>T (p.Arg77Cys)]

NM_001080453.3(INTS1):c.229C>T (p.Arg77Cys)

Gene:

INTS1:integrator complex subunit 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p22.3

Genomic location:

Preferred name:

NM_001080453.3(INTS1):c.229C>T (p.Arg77Cys)

HGVS:

NC_000007.14:g.1503021G>A
NM_001080453.3:c.229C>TMANE SELECT
NP_001073922.2:p.Arg77Cys
NC_000007.13:g.1542657G>A
NM_001080453.2:c.229C>T

Protein change:

R77C; ARG77CYS

Links:

OMIM: 611345.0002; dbSNP: rs200649090

NCBI 1000 Genomes Browser:

rs200649090

Molecular consequence:

NM_001080453.3:c.229C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies
Identifiers:: MONDO: MONDO:0032817; MedGen: C5231414; OMIM: 618571

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000992441	OMIM	no assertion criteria provided	Pathogenic (Sep 11, 2019)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001441634	Shieh Lab, University of California, San Francisco	no assertion criteria provided	Pathogenic (Oct 19, 2020)	germline	research
SCV003834956	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 7, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000992441

OMIM

no assertion criteria provided

Pathogenic
(Sep 11, 2019)

germline

literature only

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

SCV001441634

Shieh Lab, University of California, San Francisco

no assertion criteria provided

Pathogenic
(Oct 19, 2020)

germline

research

SCV003834956

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(May 7, 2021)

unknown

clinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Biallelic sequence variants in INTS1 in patients with developmental delays, cataracts, and craniofacial anomalies.

Krall M, Htun S, Schnur RE, Brooks AS, Baker L, de Alba Campomanes A, Lamont RE, Gripp KW; Care 4 Rare Canada Consortium., Schneidman-Duhovny D, Innes AM, Mancini GMS, Slavotinek AM.

Eur J Hum Genet. 2019 Apr;27(4):582-593. doi: 10.1038/s41431-018-0298-9. Epub 2019 Jan 8.

PubMed [citation]

PMID:: 30622326
PMCID:: PMC6460580

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 OMIM, SCV000992441.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 2 brothers (patients 1 and 2) of Hispanic descent with neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies (NDCAGF; 618571), Krall et al. (2019) identified compound heterozygous mutations in the INTS1 gene: a c.229C-T transition (c.229C-T, NM_001080453.2), resulting in an arg77-to-cys (R77C) substitution, and a 1-bp duplication (c.5398dupC; 611345.0003), resulting in a frameshift and premature termination (Arg1800ProfsTer20). The mutations were found by exome sequencing and confirmed by Sanger sequencing. The c.229C-T variant was found at a low frequency in the ExAC (0.02494) and gnomAD (0.0002059) databases; the 1-bp duplication was not found in ExAC, but was found at a low frequency in the gnomAD database (7.21 x 10(-6)). The R77C variant was present in homozygous state in 1 patient of Hispanic descent in the gnomAD database, suggesting that it may be a hypomorphic variant and only pathogenic when combined with a truncating variant. Functional studies of the variant and studies of patient cells were not performed.

#	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		not provided	not provided	not provided	not provided

From Shieh Lab, University of California, San Francisco, SCV001441634.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV003834956.1

#	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

Last Updated: May 1, 2024

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