NM_000350.3(ABCA4):c.3344T>C (p.Met1115Thr) AND not provided

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 24, 2023
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:: RCV001360658.7

Allele description [Variation Report for NM_000350.3(ABCA4):c.3344T>C (p.Met1115Thr)]

NM_000350.3(ABCA4):c.3344T>C (p.Met1115Thr)

Gene:

ABCA4:ATP binding cassette subfamily A member 4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p22.1

Genomic location:

Preferred name:

NM_000350.3(ABCA4):c.3344T>C (p.Met1115Thr)

HGVS:

NC_000001.11:g.94041387A>G
NG_009073.1:g.84763T>C
NG_009073.2:g.84761T>C
NM_000350.3:c.3344T>CMANE SELECT
NM_001425324.1:c.3122T>C
NP_000341.2:p.Met1115Thr
NP_001412253.1:p.Met1041Thr
NC_000001.10:g.94506943A>G

Protein change:

M1041T

Links:

dbSNP: rs376947008

NCBI 1000 Genomes Browser:

rs376947008

Molecular consequence:

NM_000350.3:c.3344T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001425324.1:c.3122T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Gm39521 predicted gene, 39521 [Mus musculus]
Gm39521 predicted gene, 39521 [Mus musculus]
Gene ID:105243693

Gene
Gm39521 AND (alive[prop]) (1)
Gene
RecName: Full=Mediator of RNA polymerase II transcription subunit 21; AltName: F...
RecName: Full=Mediator of RNA polymerase II transcription subunit 21; AltName: Full=Mediator complex subunit 21; AltName: Full=RNAPII complex component SRB7; AltName: Full=Suppressor of RNA polymerase B 7
gi|1351113|sp|P47822.1|MED21_YEAST

Protein
F-actin-uncapping protein LRRC16A isoform X2 [Homo sapiens]
F-actin-uncapping protein LRRC16A isoform X2 [Homo sapiens]
gi|1034650745|ref|XP_016866498.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001556585	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 24, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31212395, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001556585

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 24, 2023)

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

Cost-effective molecular inversion probe-based ABCA4 sequencing reveals deep-intronic variants in Stargardt disease.

Khan M, Cornelis SS, Khan MI, Elmelik D, Manders E, Bakker S, Derks R, Neveling K, van de Vorst M, Gilissen C, Meunier I, Defoort S, Puech B, Devos A, Schulz HL, Stöhr H, Grassmann F, Weber BHF, Dhaenens CM, Cremers FPM.

Hum Mutat. 2019 Oct;40(10):1749-1759. doi: 10.1002/humu.23787. Epub 2019 Jun 18.

PubMed [citation]

PMID:: 31212395

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, SCV001556585.4

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

Description

For these reasons, this variant has been classified as 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. ClinVar contains an entry for this variant (Variation ID: 1052465). This missense change has been observed in individual(s) with Stargardt disease (PMID: 31212395; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs376947008, gnomAD 0.01%). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1115 of the ABCA4 protein (p.Met1115Thr).

#	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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