rs111033219

Variant names:

• chr11-77162176-G-GGCA
• rs111033219
• NM_000260.4:c.1401_1403dupGCA

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The NM_000260.4(MYO7A):​c.1401_1403dupGCA​(p.Arg467_His468insGln) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000025 in 1,602,066 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYO7A NM_000260.4 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4
• Conservation: PhyloP100: -0.859

Genes affected

MYO7A (HGNC:7606): (myosin VIIA) This gene is a member of the myosin gene family. Myosins are mechanochemical proteins characterized by the presence of a motor domain, an actin-binding domain, a neck domain that interacts with other proteins, and a tail domain that serves as an anchor. This gene encodes an unconventional myosin with a very short tail. Defects in this gene are associated with the mouse shaker-1 phenotype and the human Usher syndrome 1B which are characterized by deafness, reduced vestibular function, and (in human) retinal degeneration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000260.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 11-77162176-G-GGCA is Pathogenic according to our data. Variant chr11-77162176-G-GGCA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43145.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=3, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.1401_1403dupGCA	p.Arg467_His468insGln	disruptive_inframe_insertion	Exon 13 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.1401_1403dupGCA	p.Arg467_His468insGln	disruptive_inframe_insertion	Exon 13 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.1401_1403dupGCA	p.Arg467_His468insGln	disruptive_inframe_insertion	Exon 13 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.1368_1370dupGCA	p.Arg456_His457insGln	disruptive_inframe_insertion	Exon 14 of 50	1		ENSP00000386635.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1449912 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 719580

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152154 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74316

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2

Apr 05, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg467_His468insGln variant in MYO7A has been reported in the heterozygous state in 2 individuals with Usher syndrome type 1 (Weston 1996). This variant w as absent from large population studies, though the ability of these studies to accurately detect indels may be limited. This variant is an insertion of 1 amino acid at position 467 and is not predicted to alter the protein reading-frame. I t is unclear if this insertion will impact the protein. In summary, the clinical significance of the p.Arg467_His468insGln variant is uncertain. ACMG/AMP Criter ia applied: PM2; PM4_Supporting. -

Apr 17, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYO7A c.1401_1403dupGCA (p.Arg467_His468insGln) results in an in-frame insertion that is predicted to insert one amino acid into the Myosin head, motor domain (IPR001609) of the encoded protein. The variant was absent in 230428 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1401_1403dupGCA has been reported in the literature as a non-informative heterozygous genotype (without a second allele specified) in an affected proband with Usher syndrome as well as in her unaffected mother and unaffected maternal grandmother (Weston_1996). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16963483, 20146813, 9718356, 8900236). ClinVar contains an entry for this variant (Variation ID: 43145). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Pathogenic:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.1401_1403dup, results in the insertion of 1 amino acid(s) of the MYO7A protein (p.Arg467_His468insGln), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of autosomal recessive MYO7A-related conditions (PMID: 8900236; internal data). This variant is also known as 468+Gln. ClinVar contains an entry for this variant (Variation ID: 43145). For these reasons, this variant has been classified as Pathogenic. -

Usher syndrome type 1;C1832475:Autosomal dominant nonsyndromic hearing loss 11;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1

Apr 27, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1

Jun 19, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1B Uncertain:1

Jul 20, 2021

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs111033219; hg19: chr11-76873222;