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NM_015166.4(MLC1):c.274C>T (p.Pro92Ser) AND not provided

Germline classification:
Likely pathogenic (2 submissions)
Last evaluated:
Jan 14, 2024
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:
RCV001378687.12

Allele description

NM_015166.4(MLC1):c.274C>T (p.Pro92Ser)

Gene:
MLC1:modulator of VRAC current 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
22q13.33
Genomic location:
Preferred name:
NM_015166.4(MLC1):c.274C>T (p.Pro92Ser)
HGVS:
  • NC_000022.11:g.50080391G>A
  • NG_009162.1:g.10539C>T
  • NM_001376472.1:c.274C>T
  • NM_001376473.1:c.274C>T
  • NM_001376474.1:c.274C>T
  • NM_001376475.1:c.274C>T
  • NM_001376476.1:c.274C>T
  • NM_001376477.1:c.274C>T
  • NM_001376478.1:c.274C>T
  • NM_001376479.1:c.274C>T
  • NM_001376480.1:c.184C>T
  • NM_001376481.1:c.274C>T
  • NM_001376482.1:c.267+2693C>T
  • NM_001376483.1:c.267+2693C>T
  • NM_001376484.1:c.37C>T
  • NM_015166.4:c.274C>TMANE SELECT
  • NM_139202.3:c.274C>T
  • NP_001363401.1:p.Pro92Ser
  • NP_001363402.1:p.Pro92Ser
  • NP_001363403.1:p.Pro92Ser
  • NP_001363404.1:p.Pro92Ser
  • NP_001363405.1:p.Pro92Ser
  • NP_001363406.1:p.Pro92Ser
  • NP_001363407.1:p.Pro92Ser
  • NP_001363408.1:p.Pro92Ser
  • NP_001363409.1:p.Pro62Ser
  • NP_001363410.1:p.Pro92Ser
  • NP_001363413.1:p.Pro13Ser
  • NP_055981.1:p.Pro92Ser
  • NP_055981.1:p.Pro92Ser
  • NP_631941.1:p.Pro92Ser
  • NC_000022.10:g.50518820G>A
  • NM_001376474.1:c.274C>T
  • NM_015166.3:c.274C>T
  • NR_164811.1:n.621C>T
  • NR_164812.1:n.405C>T
  • NR_164813.1:n.798C>T
  • Q15049:p.Pro92Ser
Protein change:
P13S; PRO92SER
Links:
UniProtKB: Q15049#VAR_017439; OMIM: 605908.0007; dbSNP: rs121908345
NCBI 1000 Genomes Browser:
rs121908345
Molecular consequence:
  • NM_001376482.1:c.267+2693C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001376483.1:c.267+2693C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001376472.1:c.274C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001376473.1:c.274C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001376474.1:c.274C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001376475.1:c.274C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001376476.1:c.274C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001376477.1:c.274C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001376478.1:c.274C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001376479.1:c.274C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001376480.1:c.184C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001376481.1:c.274C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001376484.1:c.37C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_015166.4:c.274C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139202.3:c.274C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_164811.1:n.621C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_164812.1:n.405C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_164813.1:n.798C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Observations:
1

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001576310Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Jan 14, 2024) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV004153338CeGaT Center for Human Genetics Tuebingen
criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)		Likely pathogenic
(Oct 1, 2023) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Identification of novel mutations in MLC1 responsible for megalencephalic leukoencephalopathy with subcortical cysts.

Leegwater PA, Boor PK, Yuan BQ, van der Steen J, Visser A, Könst AA, Oudejans CB, Schutgens RB, Pronk JC, van der Knaap MS.

Hum Genet. 2002 Mar;110(3):279-83. Epub 2002 Feb 8. Erratum in: Hum Genet 2002 Jul;111(1):114.

PubMed [citation]
PMID:
11935341

Vacuolating megalencephalic leukoencephalopathy with subcortical cysts: functional studies of novel variants in MLC1.

Montagna G, Teijido O, Eymard-Pierre E, Muraki K, Cohen B, Loizzo A, Grosso P, Tedeschi G, Palacín M, Boespflug-Tanguy O, Bertini E, Santorelli FM, Estévez R.

Hum Mutat. 2006 Mar;27(3):292.

PubMed [citation]
PMID:
16470554
See all PubMed Citations (6)

Details of each submission

From Invitae, SCV001576310.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 92 of the MLC1 protein (p.Pro92Ser). This variant is present in population databases (rs121908345, gnomAD 0.2%). This missense change has been observed in individuals with megalencephalic leukoencephalopathy with subcortical cysts (PMID: 11935341, 16470554, 21145992). ClinVar contains an entry for this variant (Variation ID: 4719). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLC1 protein function. Experimental studies have shown that this missense change affects MLC1 function (PMID: 18757878, 23793458). 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From CeGaT Center for Human Genetics Tuebingen, SCV004153338.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

MLC1: PM2, PM3, PM5, PP4, PS3:Supporting

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Aug 4, 2024