NM_000350.3(ABCA4):c.4861A>T (p.Asn1621Tyr) AND not provided

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 28, 2022
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:: RCV003832341.2

Allele description [Variation Report for NM_000350.3(ABCA4):c.4861A>T (p.Asn1621Tyr)]

NM_000350.3(ABCA4):c.4861A>T (p.Asn1621Tyr)

Genes:

ABCA4:ATP binding cassette subfamily A member 4 [Gene - OMIM - HGNC]
LOC126805793:CDK7 strongly-dependent group 2 enhancer GRCh37_chr1:94486302-94487501 [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

1p22.1

Genomic location:

Preferred name:

NM_000350.3(ABCA4):c.4861A>T (p.Asn1621Tyr)

HGVS:

NC_000001.11:g.94021397T>A
NG_009073.2:g.104751A>T
NG_082117.1:g.752T>A
NM_000350.3:c.4861A>TMANE SELECT
NM_001425324.1:c.4639A>T
NP_000341.2:p.Asn1621Tyr
NP_001412253.1:p.Asn1547Tyr
NC_000001.10:g.94486953T>A
NG_009073.1:g.104753A>T

Protein change:

N1547Y

Molecular consequence:

NM_000350.3:c.4861A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001425324.1:c.4639A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004640346	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 28, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32037395, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004640346

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 28, 2022)

germline

clinical testing

PubMed (2)
[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

Citations

PubMed

Copy-number variation contributes 9% of pathogenicity in the inherited retinal degenerations.

Zampaglione E, Kinde B, Place EM, Navarro-Gomez D, Maher M, Jamshidi F, Nassiri S, Mazzone JA, Finn C, Schlegel D, Comander J, Pierce EA, Bujakowska KM.

Genet Med. 2020 Jun;22(6):1079-1087. doi: 10.1038/s41436-020-0759-8. Epub 2020 Feb 10.

PubMed [citation]

PMID:: 32037395
PMCID:: PMC7272325

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004640346.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA4 protein function. This missense change has been observed in individual(s) with inherited retinal dystrophy and/or Stargardt disease (PMID: 32037395; Invitae). This variant is present in population databases (rs775170464, gnomAD 0.0009%). This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 1621 of the ABCA4 protein (p.Asn1621Tyr).

#	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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